Archive for February, 2013

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Posted in Atherogenic Processes & Pathology, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Human Immune System in Health and in Disease, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged Aviva Lev-Ari, Cardiac muscle, Cardiovascular disease, Heart disease, Stem cell, Thymosin on February 28, 2013| 14 Comments »

Heart Vasculature – Regeneration and Protection of Coronary Artery Endothelium and Smooth Muscle: A Concept-based Pharmacological Therapy of a Combination Three Drug Regimen including THYMOSIN

Author & Curator: Aviva Lev-Ari, PhD, RN

ABSTRACT

A concept-based original pharmacological therapy was developed for the research results presented in Cell by Wu, Fujiwara, Cibulsky et al. (2006), Moretti, Caron, Nakano, et al. (2006) and for the research results in Nature by Smart, Risebro, Melville, et al. (2007). We propose the following concept-based original pharmacological therapy design for Preoperative and Postoperative management of cardiac injury to heart tissue, smooth muscle, to aorta and coronary artery disease. This is a treatment for Coronary Vasculogenesis, Anti-hypertention (short-acting), Vascular Anti-inflammation (vasculitis), Neovascularization of ischemic tissue and release of adult epicardium from a quiescent state while restoring its pluripotency.

VIEW VIDEO

What are Induced Pluripotent Stem Cells? (iPS Cells)

http://www.youtube.com/watch?v=i-QSurQWZo0

Lasker Lecture: Dr. Shinya Yamanaka, 2 of 3:

Induced Pluripotent Stem Cells? (iPS Cells)

http://www.youtube.com/watch?v=DQNoyDwCPzM

Multipotent Embryonic Isl1^+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification

Alessandra A Moretti, Leslie L Caron, Atsushi A Nakano, Jason T JT Lam, Alexandra A Bernshausen,Yinhong Y Chen, Yibing Y Qyang, Lei L Bu, Mika M Sasaki, Silvia S Martin-Puig, Yunfu Y Sun, Sylvia M SM Evans, Karl-Ludwig KL Laugwitz, Kenneth R KR Chien
Cell 127(6):15 (2006), PMID 17123592

Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1^+ precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1^+ cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1^+/Nkx2.5^+/flk1^+ defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1^+ cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types.

http://pubget.com/paper/17123592/Multipotent_Embryonic_Isl1___Progenitor_Cells_Lead_to_Cardiac__Smooth_Muscle__and_Endothelial_Cell_Diversification

Thymosin beta 4 (Tβ4)

is a highly conserved, 43-amino acid acidic peptide (pI 4.6) that was first isolated from bovine thymus tissue over 25 years ago. It is present in most tissues and cell lines and is found in high concentrations in blood platelets, neutrophils, macrophages, and other lymphoid tissues. Tβ4 has numerous physiological functions, the most prominent of which being the regulation of actin polymerization in mammalian nucleated cells and with subsequent effects on actin cytoskeletal organization, necessary for cell motility, organogenesis, and other important cellular events.

Recently,

Tβ4 was shown to be expressed in the developing heart and found to stimulate migration of cardiomyocytes and endothelial cells, promote survival of cardiomyocytes (Nature, 2004), and most recently
to play an essential role in all key stages of cardiac vessel development: vasculogenesis, angiogenesis, and arteriogenesis (Nature 2006).
These results suggest that Tβ4 may have significant therapeutic potential in humans to protect myocardium and promote cardiomyocyte survival in the acute stages of ischemic heart disease.

RegeneRx Biopharmaceuticals, Inc. is developing Tβ4 for the treatment of patients with acute myocardial infarction (AMI). Such efforts presented will include the formulation, development, and manufacture of a suitable drug product for use in the clinic, the performance of nonclinical pharmacology and toxicology studies, and the implementation of a phase 1 clinical protocol to assess the safety, tolerability, and the pharmacokinetics of Tβ4 in healthy volunteers.

http://onlinelibrary.wiley.com/doi/10.1196/annals.1415.051/abstract;jsessionid=BB7CC897572B7DDB60370EA64A81FC3F.d01t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false

EXPLORATIONS with THYMOSIN beta4 for INDUCING ADULT EPICARDIAL PROGENETOR MOBILIZATION AND NEOVASCULARIZATION is presented in

Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

http://pharmaceuticalintelligence.com/2012/04/30/93/

EXPLORATIONS with THYMOSIN beta4 for INDUCTION of ARTERIOGENESIS, Prevention and repair of damaged cardiac tissue post MI and other CVD related research projects are presented in

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

Recent research results with THYMOSIN beta4 in use for Cardiovascular Disease

appeared in 2010:

Thymosins in Health and Disease: 2nd International Symposium,

Annals of the New York Academy of Sciences, May 2010 Volume 1194 Pages ix–xi, 1–230

http://onlinelibrary.wiley.com/doi/10.1111/nyas.2010.1194.issue-1/issuetoc

appeared in 2012:

Thymosins in Health and Disease II: 3^rd International Symposium on The Emerging Clinical Applications of Tymosin beta 4 in Cardiovascular Disease

Annals of the New York Academy of Sciences, October 2012 Volume 1270 Pages vii-ix, 1–121.

http://onlinelibrary.wiley.com/doi/10.1111/nyas.2012.1270.issue-1/issuetoc

Allan L. Goldstein, Enrico Garaci, Editors, Thymosins in Cardiovascular Disease, November 2012, Wiley-Blackwell (paperback)

http://www.wiley.com/WileyCDA/WileyTitle/productCd-1573319104.html?cid=RSS_WILEY2_LIFEMED

Selected for this article are the abstracts of the following research projects, all were presented at the 2^nd International Symposium, May 2010:

Thymosin β4: structure, function, and biological properties supporting current and future clinical applications

Published studies have described a number of physiological properties and cellular functions of thymosin β4 (Tβ4), the major G-actin-sequestering molecule in mammalian cells. Those activities include the promotion of cell migration, blood vessel formation, cell survival, stem cell differentiation, the modulation of cytokines, chemokines, and specific proteases, the upregulation of matrix molecules and gene expression, and the downregulation of a major nuclear transcription factor. Such properties have provided the scientific rationale for a number of ongoing and planned dermal, corneal, cardiac clinical trials evaluating the tissue protective, regenerative and repair potential of Tβ4, and direction for future clinical applications in the treatment of diseases of the central nervous system, lung inflammatory disease, and sepsis. A special emphasis is placed on the development of Tβ4 in the treatment of patients with ST elevation myocardial infarction in combination with percutaneous coronary intervention, pp.179-189, May 2010.

Thymosin β4 and cardiac repair

Hypoxic heart disease is a predominant cause of disability and death worldwide. As adult mammals are incapable of cardiac repair after infarction, the discovery of effective methods to achieve myocardial and vascular regeneration is crucial. Efforts to use stem cells to repopulate damaged tissue are currently limited by technical considerations and restricted cell potential. We discovered that the small, secreted peptide thymosin β4 (Tβ4) could be sufficiently used to inhibit myocardial cell death, stimulate vessel growth, and activate endogenous cardiac progenitors by reminding the adult heart on its embryonic program in vivo. The initiation of epicardial thickening accompanied by increase of myocardial and epicardial progenitors with or without infarction indicate that the reactivation process is independent of injury. Our results demonstrate Tβ4 to be the first known molecule able to initiate simultaneous myocardial and vascular regeneration after systemic administration in vivo. Given our findings, the utility of Tβ4 to heal cardiac injury may hold promise and warrant further investigation, pp. 87-96, May 2010.

Thymosin β4 facilitates epicardial neovascularization of the injured adult heart

Ischemic heart disease complicated by coronary artery occlusion causes myocardial infarction (MI), which is the major cause of morbidity and mortality in humans

http://www.who.int/cardiovascular_diseases/resources/atlas/en/index.html

After MI the human heart has an impaired capacity to regenerate and, despite the high prevalence of cardiovascular disease worldwide, there is currently only limited insight into how to stimulate repair of the injured adult heart from its component parts. Efficient cardiac regeneration requires the replacement of lost cardiomyocytes, formation of new coronary blood vessels, and appropriate modulation of inflammation to prevent maladaptive remodeling, fibrosis/scarring, and consequent cardiac dysfunction. Here we show that thymosin β4 (Tβ4) promotes new vasculature in both the intact and injured mammalian heart. We demonstrate that limited EPDC-derived endothelial-restricted neovascularization constitutes suboptimal “endogenous repair,” following injury, which is significantly augmented by Tβ4 to increase and stabilize the vascular plexus via collateral vessel growth. As such, we identify Tβ4 as a facilitator of cardiac neovascularization and highlight adult EPDCs as resident progenitors which, when instructed by Tβ4, have the capacity to sustain the myocardium after ischemic damage, pp. 97-104, May 2010.

Thymosin β4: a key factor for protective effects of eEPCs in acute and chronic ischemia

Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI-3K/Akt-dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre-treatment with thymosin β4 shRNA was performed. Thymosin ß4 peptide retroinfusion mimicked the eEPC-derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin ß4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin ß4 dependent manner, pp. 105-111, May 2010.

Clinical Study Data of Thymosin beta 4 Presented

Published on October 3, 2009 at 5:10 AM

REGENERX BIOPHARMACEUTICALS, INC. (NYSE Amex:RGN) today reported on several clinical studies with Thymosin beta 4 (Tβ4) presented the Second International Symposium on Thymosins in Health and Disease, in Catania, Italy. The following are synopses of the presentations:

Myocardial Development of RGN-352 (Injectable Tβ4 Peptide)

David Crockford, RegeneRx’s vice president for clinical and regulatory affairs presented an overview of the biological properties that support Tβ4’s near term and long term clinical applications. Mr. Crockford noted that special emphasis is being placed on the development of RGN-352 for the systemic (injectable) treatment of patients with ST-elevation myocardial infarction (STEMI) in combination with percutaneous coronary intervention, the current standard of care in most western countries for this common type of heart attack. The goal with RGN-352 is to prevent or repair continued damage to cardiac tissue post-heart attack, when such tissue around the damaged site remains at risk.

Dr. Dennis Ruff, vice president and medical director of ICON, and principal investigator, presented the most current results on the Phase I safety study with RGN-352 entitled, “A Randomized, Double-blind, Placebo-controlled, Dose-response Phase I Study of the Safety and Tolerability of the Intravenous Administration of Thymosin Beta 4 and its Pharmacokinetics After Single and Multiple Doses in Healthy Volunteers.” Dr. Ruff discussed key aspects of the study and concluded with, “There were no dose limiting or serious adverse events throughout the dosing period. Synthetic Tβ4 administered intravenously up to 1260 mg, and for up to 14 days, appears to be well tolerated with low incidence of adverse events and no evidence of serious adverse events.”

http://www.news-medical.net/news/20091003/Clinical-study-data-of-Thymosin-beta-4-presented.aspx

RegeneRx Receives Notice of Allowance from Chinese Patent Office for Treatment and Prevention of Heart Disease

RegeneRx Receives Notice of Allowance from Chinese Patent Office for Treatment and Prevention of Heart Disease

February 7, 2013 — Rockville, MD

RegeneRx Biopharmaceuticals, Inc. (OTC Bulletin Board: RGRX) (“the Company” or “RegeneRx”) today announced that it has received a Notice of Allowance of a Chinese patent application for uses of Thymosin beta 4 (TB4) for treating, preventing, inhibiting or reducing heart tissue deterioration, injury or damage in a subject with heart failure disease. Claims also include uses for restoring heart tissue in those subjects. The patent will expire July 26, 2026 http://www.regenerx.com/wt/page/pr_1360265259

Theoretical treatment protocol differential between the Preoperative which may be between 3 to 6 month, and the Postoperative which may prolong to one year.

Proposal for Preoperative Treatment – Three drug combination involves

Drug # 1: Thymosin fraction 5 (a sublingual composition)
Drug # 2: Indomethacin (Nonsteroidal anti-inflammatory drugs (NSAID))
Drug # 3: Clevidipine (blood pressure lowering drug, (no effect on heart rate))

Proposal for Postoperative Treatment – Three drug combination consists of

Drug # 1: Thymosin fraction 5 (a sublingual composition)
Drug # 4: ACEI (Captopril (50mg))
Drug # 5: Beta Blocker and Diuretic (Metoprolol and hydrochlorothiazide (50 mg/25 mg)) Lopressor HCT

Unprecedented novel paradigm development in the scientific understanding of the origin of

(a) myocardial cells
(b) smooth muscle cells
(c) endothelial cells
(d) pace maker cells and
(e) heart vasculature: aorta, pulmonary artery and coronary arteries, occurred in 2006.

In a seminal article in Cell, “Developmental Origin of a Bipotential Myocardial and Smooth Muscle Cell Precursor in the Mammalian Heart” Wu, et al., (2006), described their discovery as follows:

“Despite recent advances in delineating the mechanisms involved in cardiogenesis, cellular lineage specification remains incompletely understood.” To explore the relationship between developmental fate and potential.” They “isolated a cardiac-specific Nkx2.5+ cell population from the developing mouse embryo. The majority of these cells differentiated into cardiomyocytes and conduction system cells. Some, surprisingly, adopted a smooth muscle fate. To address the clonal origin of these lineages, we isolated Nkx2.5+ cells from in vitro differentiated murine embryonic stem cells and found ~28% of these cells expressed c-kit. These c-kit+ cells possessed the capacity for long-term in vitro expansion and differentiation into both cardiomyocytes and smooth muscle cells from a single cell.” They “confirmed these findings by isolating c-kit+Nkx2.5+ cells from mouse embryos and demonstrated their capacity for bipotential differentiation in vivo. Taken together, these results support the existence of a common precursor for cardiovascular lineages in the mammalian heart.”

Another breakthrough article in Cell, “Multipotent Embryonic Isl1+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification” Moretti, et al., (2006) described their discovery as follows:

“Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors.” They “use genetic fate-mapping studies to document that isl1+ precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells”, they “clonally amplified a cellular hierarchy of isl1+ cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1+/Nkx2.5+/flk1+ defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1+ cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types.” (Moretti, et al., 2006).

Third scientific breakthrough was reported in Nature on the roles that Thymosin beta4 play in

(a) coronary vessel development
(b) induction of adult epicardial cell migration
(c) cardiomyocyte survival by vascularization which is dependent on Thymosin beta4 and
(d) identification of the pro-angiogenic tetrapeptide AcSDKP which is produced by endoproteinase activity of Thymosin beta4 (Smart, et al., 2007).

That new level of understanding has the potential to generate new pharmaco therapies to upregulate biological processes that underlie the function of the various compartments of the cardiovascular system, as new scientific explanations became available in 2006.

We have developed a methodology for discovery of concept-based original pharmacological therapy designs for combination of several drug regimens. We carry out two types of research strategy. Methodology Strategy Type One: we develop an original pharmacological therapy design specialized in addressing medical problems identified in targeted follow up studies on mortality and morbidity of cardiovascular patients. Methodology Strategy Type One is implemented in Lev-Ari & Abourjaily (2006a, 2006b, 2006c). We designed a specialized pharmaco therapy for the research results presented in NEJM, on “Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes” (Werner, Kosiol, Schiegl, et al., 2005a) and the editorial interpretation of these research results by Rosenzweig (2005). We proposed the following concept-based original pharmacological therapy design for Endogenous Augmentation of circulating Endothelial Progenitor Cells for Reduction of Risk for Macrovascular Cardiac Events.

Proposal of Treatment – Three drug combination

Inhibition of ET-1, ET_A and ET_A-ET_B(Bosentan)
Induction of NO production and stimulation of eNOS (Nebivolol)
Stimulation of PPAR-gamma (substitute to Rosiglitazone)

Our Methodology Strategy Type Two involves discovery of concept-based original pharmacological therapy design for combination of several drug regimens for underlying biological processes discovered in the pursuit of basic researchers conducted in wet lab experiments by vascular biologists and molecular cardiologists. Here, we developed a concept-based original pharmacological therapy for the research results presented in Cell by Wu, Fujiwara, Cibulsky et al. (2006), Moretti, Caron, Nakano, et al. (2006) and for the research results in Nature by Smart, Risebro, Melville, et al. (2007). We propose the following concept-based original pharmacological therapy design for Preoperative and Postoperative management of cardiac injury to heart tissue, smooth muscle and to aorta and coronary artery disease. This is a treatment for Coronary Vasculogenesis, Anti-hypertention (short-acting), Vascular Anti-inflammation (vasculitis), Neovascularization of ischemic tissue and release of adult epicardium from a quiescent state and restoring its pluripotency.

Proposal for Preoperative Treatment – Three drug combination

Drug # 1:

Thymosin fraction 5 (a sublingual composition)

Drug # 2:

Indomethacin (Nonsteroidal anti-inflammatory drugs (NSAID))

Drug # 3:

Clevidipine (blood pressure lowering drug, no effect on heart rate)

Proposal for Postoperative Treatment – Three drugs combination

Drug # 1:

Thymosin fraction 5 (a sublingual composition)

Drug # 4:

ACEI (Captopril (50mg))

Drug # 5:

HCTBeta Blocker and Diuretic (Metoprolol and hydrochlorothiazide (50 mg/25 mg)) Lopressor

Thymosin beta4 Induces Adult Epicardial Progenitor Mobilization and Neovascularization

Smart et al. (2007) implicate Thymosine beta4 (Tb4) with the following functions: (a) Tb4 in regulating all three key stages of cardiac vessel development: coronary vasculogenesis, angiogenesis and arteriogenesis – collateral growth; (b) identify the adult epicardium as a potential source of vascular progenitors which, when stimulated by Tb4, migrate and differentiate into smooth muscle and endothelial cells; (c) the ability of Tb4 to promote coronary vascularization both during development and in the adult, enhances cardiomyocyte survival and contributes significantly towards Tb4-induced cardioprotection.

The reaction in the scientific community to these investigative results was most favorable.

“These results are very exciting because most humans suffering from ischemic cardiac events, either acutely or chronically, do not develop the collateral vessel growth necessary to preserve and restore heart tissue. If, in humans, we see the same effects as seen in mice, TB4 would be the first drug to prevent loss of (heart) muscle cells and restore blood flow in this manner and provide a new and much needed treatment modality for these patients,”

commented Deepak Srivastava, M.D., Professor and Director, Gladstone Institute of Cardiovascular Disease, University of California San Francisco, CA. Dr. Srivastava and his colleagues published the first paper on TB4’s effects on myocardial infarction in Nature in November 2004.

http://phx.corporate-ir.net/phoenix.zhtml?c=144396&p=irol-newsArticle&ID=932573&highlight=

VIEW VIDEO

http://www.youtube.com/watch?v=Vjj7LSuSMAo

Review of the Chemistry and the Mechanism of action supporting the process by which, N-acetyl-seryl-aspartyl-lysyl- proline (Ac-SDKP) stimulates endothelial cell differentiation from adult epicardium, is presented in

Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

http://pharmaceuticalintelligence.com/2012/04/30/93/

A Concept-based Pharmacologic Therapy of a Combined Three Drug Regimen for Regeneration and Protection of Coronary Artery Endothelium and Smooth Muscle.

This is a treatment for Coronary Vasculogenesis, Anti-hypertention (short-acting), Vascular Anti-inflammation (vasculitis), Neovascularization of ischemic tissue and release of adult epicardium from a quiescent state and restoring its pluripotency.

Preoperative Treatment – Three drugs

Drug # 1:
Thymosin fraction 5 (a sublingual composition)
Drug # 2:
Indomethacin (Nonsteroidal anti-inflammatory drugs (NSAID)) (25 mg PO bid)
Drug # 3:
Clevidipine (Blood pressure lowering drug, no effect on heart rate)

Postoperative Treatment – Three drugs

Drug # 1:
Thymosin fraction 5 (a sublingual composition)
Drug # 4:
ACEI (Captopril (50mg))
Drug # 5:
Beta Blocker and diuretic (Metoprolol and hydrochlorothiazide (50 mg/25 mg)) Lopressor HCT

Original Drug Therapy Combination Proposed

Drug # 1: Thymosin fraction 5

Drug # 2: Indomethacin

Drug # 3: Clevidipine

Drug # 1:

Sublingual compositions comprising Thymosin fraction 5

United States Patent: 6,733,791

http://www.pharmcast.com/Patents100/Yr2004/May2004/051104/6733791_Sublingual051104.htm

http://www.google.com/patents/US6733791

The compositions comprise a room temperature stable peptide or complex of peptides that may be administered in a dosage of between 0.0001 mg/ml or gm and 600 mg/ml or gm.

Thymosin beta4 is released from human blood platelets and attached by factor XIIIa (transglutaminase) to fibrin and collagen (Huff et al. 2002). They suggest that Thymosin beta4 cross-linking is mediated by factor XIIIa, a transglutaminase that is co-released from stimulated platelets. This provides a mechanism to increase the local concentration of Thymosin beta4 near sites of clots and tissue damage, where it may contribute to wound healing, angiogenesis and inflammatory responses (Al-Nedawi, et al., 2004). The beta-Thymosins constitute a family of highly conserved and extremely water-soluble 5 kDa polypeptides. Thymosin beta4 is the most abundant member; it is expressed in most cell types and is regarded as the main intracellular G-actin sequestering peptide. There is increasing evidence for extracellular functions of Thymosin beta4. For example, Thymosin beta4 increases the rate of attachment and spreading of endothelial cells on matrix components and stimulates the migration of human umbilical vein endothelial cells. They show that Thymosin beta4 can be cross-linked to proteins such as fibrin and collagen by tissue transglutaminase. Thymosin beta4 is not cross-linked to many other proteins and its cross-linking to fibrin is competed by another family member, Thymosin beta10 (Huff et al. 2002).

Rationale for selection of Sublingual compositions comprising Thymosin fraction 5

The actin binding motif of Thymosin beta4 is an essential site for its angiogenic activity (Philip, et al. (2003). Thymosin beta4 is presented in Smart, et al. (2007) in the Nature article as a single factor that can potentially couple myocardial and coronary vascular regeneration in failing mouse hearts. They have shown that cells in the heart’s outer layer can migrate deeper into a failing organ to carry out essential repairs. The migration of progenitor cells is controlled by the protein Thymosin beta 4, already known to help reduce muscle cell loss after a heart attack.

http://news.bbc.co.uk/2/hi/health/6143286.stm

The discovery opens up the possibility of using the protein to develop more effective treatments for heart disease. Previously it was thought that cells within the adult heart are in a state of permanent rest and that any progenitor cells that can contribute to heart tissue repair travel into the heart from the bone marrow. See 150 references on that perspective on cEPCs origin and roles, which was the scientific frontier on this topic, prior to the publication of Smart et al., (2007), in Lev-Ari & Abourjaily (2006a, 2006b, 2006c).

However, researchers at University College London have demonstrated that beneficial cells actually reside in the heart itself (Smart et al. (2007). This approach would bypass the risk of immune system rejection, a major problem with the use of stem cell transplants from another source. Allogenic rejection was the main reason for the selection of an endogenous augmentation method for cEPCs using drug therapy by Lev-Ari & Abourjaily (2006a, 2006b, 2006c). Closer examination revealed that without the Thymosin beta 4 protein, the progenitor cells failed to move deeper into the heart and change the cells needed to build healthy blood vessels and sustain muscle tissue.

http://www.irishhealth.com/clin/cholesterol/newsstory.php?id=10581

Drug # 2:

Indomethacin

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory effects and have been shown to have chemopreventive effects as well. NSAIDs inhibit cyclooxygenase (COX) activity to exert their anti-inflammatory effects, but it is not clear whether their antitumorigenic ability is through COX inhibition. Using subtractive hybridization, Jain et al. (2004) identified a novel member of the transforming growth factor- superfamily that has antitumorigenic activity from Indomethacin-treated HCT-116 human colorectal cancer cells. On further investigation of this library, they now report the identification of a new cDNA corresponding to the Thymosin beta-4 gene. Thymosin beta-4 is a small peptide that is known for its actin-sequestering function, and it is associated with the induction of angiogenesis, accelerated wound healing, and metastatic potential of tumor cells. However, only selective NSAIDs induce Thymosin beta-4 expression in a time- and concentration-dependent manner. For example,

Indomethacin and SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole] induce Thymosin beta-4 expression whereas sulindac sulfide does not.

They show that selective NSAIDs induce actin cytoskeletal reorganization, a precursory step to many dynamic processes regulating growth and motility including tumorigenesis. This is the first report to link Thymosin beta-4 induction with NSAIDs. These data suggest that NSAIDs alter the expression of a diverse number of genes and provide new insights into the chemopreventive and biological activity of these drugs (Jain et al. 2004).

Rationale for Indomethacin selection

Inhibitor of prostaglandin synthesis. Inhibits cyclooxygenase (COX) 1 selective.

Suggested dosage: 25 mg PO bid.

Jain et al. (2004) report a link between Thymosin beta-4 induction with NSAIDs. We selected both drugs (drug classes) and anticipate strong synergistic therapeutic effects.

Drug # 3:

Clevidipine

Clevidipine is the first third-generation calcium channel blocker, Dr. Papadakos said. It has what he called an “ultrashort” clinically relevant half-life of about one minute and then is rapidly metabolized. The effect on blood pressure is seen within one to two minutes.

http://www.medpagetoday.com/MeetingCoverage/SCCM/tb/5091

Clevidipine is an investigational agent undergoing late-stage clinical development to evaluate its potential as an innovative, targeted, fast acting intravenous product under investigation for lowering blood pressure before, during and after surgery.

http://www.themedicinescompany.com/products_Clevidipine.shtml

The Medicines Company entered into agreements with AstraZeneca PLC in March of 2002 for the development, licensing and commercialization of Clevidipine. If approved, the product could be an excellent fit with The Medicines Company’s emerging acute cardiovascular care franchise, which is led by Angiomax® (bivalirudin), an anticoagulant approved in the U.S. and other countries for use during coronary angioplasty procedures. If Clevidipine passes further clinical hurdles — phase III trials are under way — the drug may form a useful addition to the medications available to physicians in the perioperative setting

Mechanism of Action

Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. In vitro studies demonstrated that Clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in widening of the artery opening and reducing blood pressure within the artery (Levy, Huraux, Nordlander, 1997, 345-358).

Phase III Clinical Trials

The Medicines Company is currently sponsoring a Phase III clinical program of five studies to evaluate safety and efficacy of Clevidipine:

Early Development

The Medicines Company’s development program for Clevidipine follows upon the data sets generated by AstraZeneca, which completed clinical pharmacology, dose-finding and efficacy studies in almost 300 patients or volunteers. In clinical studies, Clevidipine has shown to provide the desired blood pressure lowering effect without causing an increase in heart rate (Kotrly, et al. 1984). Further studies demonstrate that reductions in blood pressure are dose-dependent, are not associated with an increase in heart rate and cease rapidly after stopping Clevidipine infusions (Ericsson, et al., 2000), (Schwieler, et al., 1999). In clinical studies Clevidipine was rapidly metabolized independent of the liver and the kidneys, allowing rapid clearance of the drug from the bloodstream (Ericsson, et al., 1999a), (Ericsson, et al., 1999b). Therefore, the effects of Clevidipine are short-lived, which translates into a rapid cessation of its effect on reducing blood pressure.

The two efficacy studies are known as ESCAPE-1 and ESCAPE-2. The primary objective of these studies is to determine the efficacy of Clevidipine injection versus placebo in treating pre-operative (ESCAPE-1) and post-operative (ESCAPE-2) high blood pressure. Three safety studies are collectively known as ECLIPSE. The primary objective is to establish the safety of Clevidipine in the treatment of perioperative high blood pressure, as measured by a comparison of the incidences of death, stroke, myocardial infarction and renal dysfunction between the Clevidipine and comparative treatment groups. The comparative treatments are nitroglycerin, sodium nitroprusside and nicardipine. The ECLIPSE trial randomized 589 patients at 40 centers in the U.S. to get either sodium nitroprusside or Clevidipine. Sodium nitroprusside was administered according to institutional practice; Clevidipine was begun at 2 mg/kg and doubled every 90 seconds until blood pressure was lowered. The primary endpoint was the difference in major clinical events — death, myocardial infarction, stroke, and renal dysfunction 30 days after surgery. The secondary endpoint was blood pressure control during the first 24 hours after surgery.

The study showed no significant differences in the elements of the primary endpoint, except for mortality, Dr. Papadakos said, where 1.7% of Clevidipine patients died, compared with 4.7 of those getting sodium nitroprusside. The difference was statistically significant at P<0.05, but Dr. Papadakos characterized the improvement as “slight.” On the other hand, the drug did show an important difference in blood pressure control over the first 24 hours, he said:

Patients on Clevidipine spent an average of 4.37 minutes per hour outside the desired blood pressure range.
Sodium nitroprusside patients spent, on average, 10.5 minutes per hour outside the desired range.
The difference was statistically significant at P<0.003.

Dr. Papadakos concluded that Clevidipine is a new drug that is effective, safe, and easy to use. On 2/20/2007, Dr. Deutschman, who moderated the late-breaking session at which Dr. Papadakos spoke, said that a better comparison, would be intravenous nicardipine (Cardene IV), a second-generation calcium channel blocker that is also in wide use and is considered the standard of care. “We don’t know yet if this drug is going to be better than nicardipine,” he said.

http://www.medpagetoday.com/MeetingCoverage/SCCM/tb/5091

Rationale for Clevidipine selection

Clevidipine is an acute care product. Blood pressure management is a major component of care during the 13.4 million inpatient surgeries conducted in the U.S. each year. Blood pressure control, which is managed by an anesthesiologist, is often important in patients with both normal and high blood pressure undergoing surgery or other interventional procedures. Some of these patients require rapid, precise control of blood pressure to avoid compromising key organ function such as the heart, brain and kidney.

CONCLUSION

This is the first study to design a novel combination drug treatment for Coronary Vasculogenesis, Anti-hypertention (short-acting), Vascular Anti-inflammation (vasculitis), Neovascularization of ischemic tissue and release of adult epicardium from a quiescent state and restoring its pluripotency. This treatment is based on the new three paradigms that were presented in Cell (2006) and Nature (2007). This combination drug therapy of three drugs, one in current use (Indomethacin), and two in clinical trials (Thymosin beta4 & Clevidipine), has not been proposed before. It represents an original concept drug combination design by Lev-Ari & Abourjaily (2007). This combination represents the cutting edge conceptualization of the field of treatment of cardiac injury based on a protein produced in the heart cells, Thymosin beta4, which function as a tissue and artery healer. Its upregulation by drug therapy will revolutionize cardiology and treatment for cardiovascular disease. The combination drug therapy consists of the following drugs:

Drug # 1:

Thymosin fraction 5 (a sublingual composition)

Drug # 2:

Indomethacin (Nonsteroidal anti-inflammatory drugs (NSAID)) (25 mg PO bid)

Drug # 3:

Clevidipine (Blood pressure lowering drug, (no effect on heart rate))

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MGH’s Largest-ever Genetic Study of Five Psychiatric Disorders: Variation in SNPs in Two Genes involved in Calcium-Channel Signaling

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, tagged Lancet, Major depressive disorder, Massachusetts General Hospital, National Institute of Mental Health, Perelman School of Medicine, Smoller, University of Bologna on February 28, 2013| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Five Psych Disorders Have Common Genetics

By Michael Smith, North American Correspondent, MedPage Today

Published: February 27, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

share common genetic underpinnings — despite differences in symptoms and course of disease, researchers discovered.

In particular, single nucleotide polymorphisms (SNPs) in two genes involved in calcium-channel activity appear to play a role in all five, Jordan Smoller, MD, ScD, of Massachusetts General Hospital in Boston, and colleagues reported online in The Lancet.

The findings come from a genome-wide analysis of 33,332 cases and 27,888 controls in what the authors described as the largest-ever genetic study of psychiatric illness.

The results are “new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes,” Smoller said in a statement.

The findings are especially important because of revisions to the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, which have “reinvigorated debate about the validity of diagnostic boundaries,” the authors noted.

Indeed, the findings confirm previous evidence of “abundant pleiotropy in human complex disorders” – meaning the same genetic variant plays a role in several diseases, argued Alessandro Serretti, MD, PhD, and Chiara Fabbri of the University of Bologna in Italy.

For instance, they noted in an accompanying commentary, calcium signaling, a key regulator of the growth and development of neurons, was expected to be highly pleiotropic, an expectation that “has now been confirmed.”

But while some gene variants play a role in many disorders, there are almost certainly others that contribute to the “consistent diversity among disorders,” Serretti and Fabbri argued.

“Many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases,” they wrote.

Nonetheless, they concluded, one implication of the study is that genetics “can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs.”

But that is not likely to happen soon, according to Randy Ross, MD, of the University of Colorado School of Medicine in Aurora, Colo.

The study is a “beginning step to give us ideas that will eventually lead to new treatments,” he told MedPage Today.

In the long run, however, this study and subsequent research will change both diagnosis and treatment, Ross said, as psychiatric diseases are put on a biological footing.

The researchers found that SNPs (single-letter changes in the genetic code) in four regions were associated with all five disorders:

two on chromosome 10, including the L-type voltage-gated calcium-channel subunit CACNB2,
one on chromosome 3, and
another calcium-channel subunit, CACNA1C, on chromosome 12.

The statistical significance of all four surpassed the cutoff for genome-wide significance of P<5×10^-8, Smoller and colleagues reported.

The calcium-channel gene CACNA1C has been previously linked to

bipolar disorder,
schizophrenia, and
major depressive disorder, they wrote, as well as to
Timothy syndrome, a developmental disorder that can include autism.

The other calcium-channel gene has been linked to bipolar disorder in people of Han Chinese ethnicity, they added.

“Our results suggest that voltage-gated calcium signaling, and, more broadly, calcium-channel activity, could be an important biological process in psychiatric disorders,” they argued.

The region on chromosome 3 includes more than 30 genes, Smoller and colleagues noted, but previous research has linked SNPs in the area to

bipolar disorder,
schizophrenia, and
depression.

They cautioned that they compared models of cross-disorder effects with widely used goodness-of-fit measures, but different criteria might yield other results.

They also noted that diagnostic misclassification in the study cohort might produce “spurious evidence of genetic overlap between disorders,” although such errors would have to be widespread to affect the results.

Another limitation: the members of the study cohort were of European ancestry, so it’s not known if the findings apply to other populations.

The study was supported by the National Institute of Mental Health, as well as grants from the NIH, government grants from other countries, and private and foundation support.

The authors declared they had no conflicts.

The comment authors declared they had no conflicts.

Primary source: Lancet

Source reference:
Smoller JW, et al “Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis” Lancet 2013; DOI: 10.1016/S0140-6736(12)62129-1.

Additional source: Lancet
Source reference:
Alessandro Serretti, Chiara Fabbri “Shared genetics among major psychiatric disorders” Lancet 2013; DOI: 10.1016/S0140-6736(13)60223-8.

SOURCE:

http://www.medpagetoday.com/Psychiatry/GeneralPsychiatry/37584

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New Medicine and Biology Prize to follows New Physics Prize $3 Million per Scientist “a staggering sum for an individual prize”

Posted in Scientist: Career considerations, tagged Anne Wojcicki, Cornelia Bargmann, David Botstein, Eric Lander, Google, Lewis C. Cantley, Rockefeller University, Sergey Brin on February 28, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

At $3 Million, New Award Gives Medical Researchers a Dose of Celebrity

By DENNIS OVERBYE in the New York Times

Published: February 20, 2013

Eleven scientists, most of them American, were scheduled to be named on Wednesday as the first winners of the world’s richest academic prize for medicine and biology — $3 million each, more than twice the amount of the Nobel Prize.

Gonzalo Fuentes/Reuters

Yuri Milner, an entrepreneur.

Justin Sullivan/Getty Images

Sergey Brin of Google.

Enlarge This Image

Fred Prouser/Reuters

Anne Wojcicki of 23andMe, a genetics company.

Enlarge This Image

Stephen Lam/Getty Images

Mark Zuckerberg of Facebook.

The award, the Breakthrough Prize in Life Sciences, was established by four Internet titans led by Yuri Milner, a Russian entrepreneur and philanthropist who caused a stir last summer when he began giving physicists $3 million awards.

The others, whom Mr. Milner described as old friends, are Sergey Brin, a co-founder of Google; Anne Wojcicki, the founder of the genetics company 23andMe and Mr. Brin’s wife; and Mark Zuckerberg, the founder of Facebook. They plan to give five awards annually.

Ms. Wojcicki said the prize was meant to reward scientists “who think big, take risks and have made a significant impact on our lives.”

“These scientists should be household names and heroes in society,” she said.

Many of the first winners have done work on the intricate genetics of cell growth and how it can go wrong to produce cancer. The new prize was scheduled to be announced at a news conference in San Francisco, along with the following recipients:

¶Cornelia I. Bargmann, who investigates the nervous system and behavior at Rockefeller University.

¶David Botstein of Princeton University, who maps disease markers in the human genome.

¶Lewis C. Cantley of Weill Cornell Medical College, who discovered a family of enzymes related to cell growth and cancer.

¶Dr. Hans Clevers of the Hubrecht Institute in the Netherlands, who has studied how processes in adult stem cells can go wrong and cause cancer.

¶Dr. Napoleone Ferrara of the University of California, San Diego, whose work on tumor growth has led to therapies for some kinds of cancer and eye disease.

¶Titia de Lange, who works on telomeres, the protective tips on the ends of chromosomes, at Rockefeller University.

¶Eric S. Lander of the Broad Institute of Harvard and the Massachusetts Institute of Technology, a leader of theHuman Genome Project.

¶Dr. Charles L. Sawyers of Memorial Sloan-Kettering Cancer Center, who has investigated the signaling pathways that drive a cell to cancer.

¶Dr. Bert Vogelstein of Johns Hopkins University, who discovered a protein that suppresses the growth of tumors and devised a model for the progression of colon cancer that is widely used in colonoscopy.

¶Robert A. Weinberg of M.I.T., who discovered the first human oncogene, a gene that when mutated causes cancer.

¶Dr. Shinya Yamanaka of Kyoto University and the Gladstone Institutes in San Francisco, who has done groundbreaking work in developing stem cells.

In an interview, Dr. Lander said he was shocked to win the award, calling it “a staggering sum for an individual prize.”

“Their idea seems to be to grab society’s attention, to send a message that science is exciting, important, cool, our future,” he said. “It’s a very important message here in the U.S.” Dr. Lander said he would use the prize money to help pay for new approaches to teaching biology online.

The new awards are in some ways an outgrowth of Mr. Milner’s Fundamental Physics Prizes. In July, he gave $3 million each to nine theoretical physicists, and the next round is scheduled to be awarded on March 20 in Geneva.

But even as Mr. Milner was starting the physics prize, he was thinking of extending the concept to the life sciences. He reached out to Arthur D. Levinson, the chairman of Apple and a former chief executive of Genentech, the biotech company, and Dr. Levinson, in consultation with his colleagues, helped Mr. Milner select the first Breakthrough winners. These winners will form a committee that will select future winners, Mr. Milner said.

The founders said their goal was to “move the needle” of public awareness of scientists who have spent their lives advancing human knowledge.

With so much focus on sports and movie celebrities, Dr. Levinson said, the prizewinners “can share the stage with the people who on some deeper level have made important contributions.”

The founders said they hoped to attract more sponsors and increase the number of annual winners. Anyone can send a nomination to the foundation’s new Web site.

There are no age or other limits on who can win. Any number of people can share an award. And in particular, Mr. Milner said, there are no limits on how many times one individual can win. “If you’re Einstein,” he said, “you will be getting three.”

This article has been revised to reflect the following correction:

Correction: February 23, 2013

An article on Wednesday about the Breakthrough Prize in Life Sciences quoted incorrectly from comments by Eric S. Lander, one of the recipients. He called the award “a staggering sum for an individual prize,” not “a staggering amount of money for a scientist.” An accompanying picture caption repeated the erroneous phrase “a staggering amount.”

SOURCE:

http://www.nytimes.com/2013/02/20/science/new-3-million-prizes-awarded-to-11-in-life-sciences.html?_r=0

Scientists Receive a New Physics Prize

By KENNETH CHANG

Published: July 31, 2012

Physicists are rarely wealthy or famous, but a new prize rewarding research at the field’s cutting edges has made nine of them instant multimillionaires.

Yuri Milner

Simon Dawson/Bloomberg News

Yuri Milner

The nine are recipients of the Fundamental Physics Prize, established by Yuri Milner, a Russian physics student who dropped out of graduate school in 1989 and later earned billions investing in Internet companies like Facebook and Groupon.

“It knocked me off my feet,” said Alan H. Guth, a professor of physics at the Massachusetts Institute of Technology who was among the winners. He came up with the idea of cosmic inflation, that there was a period of extremely rapid expansion in the first instant of the universe.

When he was told of the $3 million prize, he assumed that the money would be shared among the winners. Not so: Instead, each of this year’s nine recipients will receive $3 million, the most lucrative academic prize in the world. TheNobel Prize currently comes with an award of $1.2 million, usually split by two or three people. The Templeton Prize, which honors contributions to understanding spiritual dimensions of life, has been the largest monetary award given to an individual, $1.7 million this year.

The $3 million has already appeared in Dr. Guth’s bank account, one that had had a balance of $200. “Suddenly, it said, $3,000,200,” he said. “The bank charged a $12 wire transfer fee, but that was easily affordable.”

Mr. Milner said that he wanted to recognize advances in delving into the deepest mysteries of physics and the universe. “This intellectual quest to understand the universe really defines us as human beings,” he said.

Four of the physicists work at the Institute for Advanced Study in Princeton, N.J.: Nima Arkani-Hamed, Juan Maldacena, Nathan Seiberg and Edward Witten. They work on theories trying to tie together the basic particles and forces of the universe, particularly with a mathematical machinery known as string theory.

The other winners are Andrei Linde, a physicist at Stanford who also worked on cosmic inflation; Alexei Kitaev, a professor of physics at the California Institute of Technology who works on quantum computers; Maxim Kontsevich, a mathematician at the Institute of Advanced Scientific Studies outside Paris whose abstract mathematical findings proved useful to physicists unraveling string theory; and Ashoke Sen, a string theorist at Harish-Chandra Research Institute in India.

Mr. Milner personally selected the inaugural group, but future recipients of the Fundamental Physics Prize, to be awarded annually, will be decided by previous winners.

He declined to explain in detail how he selected which accomplishments to honor or why all of the winners are men. “I truly see this as a start,” Mr. Milner said. “Going forward, it’s going to be up to the committee to make those considerations.”

According to the rules, the prize in future years may be split among multiple winners, and a researcher will be able to win more than once. Mr. Milner also announced that there would be a $100,000 prize to honor promising young researchers.

Unlike the Nobel in physics, the Fundamental Physics Prize can be awarded to scientists whose ideas have not yet been verified by experiments, which often occurs decades later. Sometimes a radical new idea “really deserves recognition right away because it expands our understanding of at least what is possible,” Mr. Milner said.

Dr. Arkani-Hamed, for example, has worked on theories about the origin of the Higgs boson, the particle thought to have been discovered recently at the Large Hadron Colliderin Switzerland, and about how that collider could discover new dimensions. None of his theories have been proved yet. He said several were “under strain” because of the new data.

Several of the winners said they hoped that the new prize, with its large cash award, would help raise recognition of physics and draw more students into the field. “It’ll be great to have this sort of showcase for what’s going on in the subject every year,” Dr. Arkani-Hamed said.

The winners said they had not yet decided what to do with their windfall.

“There are some rather mundane things, like paying out the mortgage,” said Mr. Kitaev, who added that he was thinking about putting some of the money into education efforts.

“My success is in large part due to good education, my teachers and the atmosphere of excitement in science when I grew up,” he said. “I might try to help restore this atmosphere as much as I can.”

Dr. Guth agreed. “I do think prizes like this help put across to the public that fundamental physics is important, and it’s not just heavyweight boxing that’s worthy of prizes,” he said.

But he was going to warn his students not to get the wrong idea. “Certainly, it’s still not a great idea to go into physics for the money,” he said.

This article has been revised to reflect the following correction:

Correction: August 1, 2012

An article on Tuesday about the new Fundamental Physics Prize misattributed a quotation by a winner about how he would spend the $3 million in prize money. It was Alexei Kitaev, a professor of physics at the California Institute of Technology — not Maxim Kontsevich, a mathematician at the Institute of Advanced Scientific Studies outside Paris who is among the eight other prizewinners — who said, in part, “There are some rather mundane things, like paying out the mortgage.” The article also gave an outdated amount for the monetary award to winners of the Nobel Prize. The prize was reduced this year to about $1.2 million, from about $1.5 million.

SOURCE:

http://www.nytimes.com/2012/07/31/science/9-scientists-win-yuri-milners-fundamental-physics-prize.html?_r=0

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Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged American Civil Liberties Union, Amicus curiae, Broad Institute, Clarence Thomas, Complementary DNA, DNA, Eric Lander, Human Genome Project, Myriad Genetics, Supreme Court, United States Supreme Court on February 27, 2013| 5 Comments »

Genomics and Ethics: DNA Fragments are Products of Nature or Patentable Genes?

Curator: Aviva Lev-Ari, PhD, RN

UPDATED 6/17/2013 – OPINIONS ON COURT DECISION of 6/13/2013

Experts say court’s decision on human gene patents is a win-win

Jun 16, 2013

Jun 16, 2013 (St. Louis Post-Dispatch – McClatchy-Tribune Information Services via COMTEX News Network) — The Supreme Court ruling Thursday that naturally occurring human genes cannot be patented effectively ended the monopoly that Utah-based Myriad Genetics had on breast and ovarian cancer tests.

The news was hailed as a victory by health advocates and medical researchers, who can now not only access the genes at issue — the BRCA1 and BRCA2 — but all other patented human genes without infringement. In the wake of the decision, several other testing companies, including Quest Diagnostics, announced it would perform the tests — and at far cheaper prices than Myriad’s.

The court’s unanimous ruling, however, was mixed. It said that naturally occurring DNA could not be patented, but synthetic DNA can still be, giving patent protection advocates and Myriad a victory, too. The decision also means that methods of isolating genes still qualify for patent protection.

The Post-Dispatch interviewed experts from a broad range of fields, from medicine to law, about the court’s ruling.

Here’s what they had to say about what was at stake and what the decision could mean.

Christopher Mason

Professor of physiology, biophysics and computational biomedicine, and author of a study showing that 41 percent of the human genome is covered by patents, Cornell University

I’d say this represents a great win for genetic liberty, both for patients and for doctors. The American Medical Association said it was a big win for patients, and I couldn’t agree more — especially for breast and ovarian cancer, but for all types of cancer. This is an important cancer gene and now it’s open for study to everyone.

(Myriad) didn’t just own a test or a method, they owned anyone’s DNA as soon as it was isolated. They didn’t say we patented a series of letters, they said we patent anything that remotely looks like that, which the court correctly said is not patentable.

It would have been great to have both the patents (on natural and synthetic DNA), but of the two this is the most restrictive one — 99.9 percent of testing is done on DNA not cDNA.

Plenty of companies aren’t scared anymore. This is going to open the floodgates on new research and ideas.

Dr. Julie Margenthaler

Associate professor of surgery and breast cancer specialist, Siteman Cancer Center

This ruling has important implications for physician scientists actively engaged in genetic research. We are on the brink of significant strides in our understanding of the genetic links to many diseases.

For those of us who care for cancer patients, personalized cancer care hinges on the ability to genetically examine the pathways that result in a normal cell becoming a malignant cell. Because some companies held patents to pieces of the genome involved when whole genome sequencing is performed, there was at least some concern over patent infringement. With this ruling, we can continue to move our research forward and benefit the lives of our current and future patients.

Michael Watson

Executive director, American College of Medical Genetics and Genomics (plaintiffs in the case), and former professor of pediatrics at Washington University

It has enormous implications for labs and the public, certainly for breast cancer and for many other cancers. Since the case was settled (Thursday), at least four labs have put the test online. Prices are about half of Myriad’s — $3,500 down to $2,000 overnight.

It’s a win-win for everybody. It used to be when you had the tests done by Myriad, you couldn’t get that test confirmed by anyone else. Now the public can confirm the test and get second opinions, and that has a lot of value for patients. And I think it’ll open up the research.

There are two aspects of this that still remain open. Because 4,000 to 5,000 genes have patents on them, many people signed licensing agreements to use the gene. One of the questions is about the contract they signed. They will probably be able to challenge their contract now.

Nathan Lakey President and CEO, Orion Genomics

I think the ruling is positive because it removes a cloud of uncertainty as to where the Supreme Court stood on patents relating to gene sequences. I appreciate the thoughtfulness that went into the ruling. Justice Thomas adds a section that talks about what the ruling did not address that’s interesting. He emphasizes that method patents, or patents covering gene sequences that apply knowledge of those sequences, are patentable. I think this is what the justices sought to do, to not limit science and to not limit innovation and improvements in patient care. I think they do a markedly good job laying out the framework by which the business of science needs to consider the issue going forward as we all seek to lower the cost of care and improve outcomes.

We’re thrilled because our patents have been crafted primarily as method patents that involve naturally occurring gene sequences, and at the same time we add on to that a novel method that was not known and is quite valuable. We have biomarkers that we believe will be able to predict the risk of an individual getting colon cancer in the future, not unlike the Myriad test, but this is for colon cancer. We feel that our path forward is actually more clear and more positive given the clear line that the Supreme Court drew around what is and what isn’t patentable.

Janet S. Hendrickson

Patent attorney, specializing in chemical, pharmaceutical and food science companies, Senniger Powers law firm

They split it down the middle, and it seems to be, when looking at the commentary, that most people agree with that. They didn’t preclude the patenting of everything related to DNA, just natural DNA.

There are so many considerations and it’s hard to know what ramifications there are going to be, and what might be the best policy. It does mean that for companies that have these claims on natural DNA in their portfolio, they need to make sure they have the other range of claims for the cDNA (synthetic DNA). For companies that have past patents, it’s going to figure into those claims for those natural DNA products.

So it’s hard to tell whether it has broader implications for other things, that when you take them out of their natural milieu we thought were patentable.

Kevin Emerson Collins Professor, Washington University School of Law and patent law expert

This is going to mean one thing for patent lawyers and another thing for biotech companies. For patent lawyers, we now have a new source of business. The court hasn’t given us precise guidelines that say exactly when in other situations do we pass from something being a product of nature to a patentable invention. That’s a new frontier that patent lawyers are going to have to advise companies on.

For biotech companies it’s going to mean they pay patent lawyers a little more. Although the Myriad Genetics ruling deals with DNA, it would seem from the language of the opinion that the ruling should also apply to nongenetic, naturally occurring materials, but exactly how is yet to be determined.

A historical example that predates the Myriad controversy is the debate over the patentability of insulin in the early 20th century. A very famous lower court opinion held that isolated and purified human insulin was patentable so long as it became isolated insulin with impurities removed and took on new commercial value. I bet that case might well come out differently under the Myriad Genetics ruling. The insulin question is moot; that patent has expired. Similarly there a number of other therapeutics which are components that nature already makes that are isolated in a way they can be used in medicine but not in their natural state. Those are the kinds of things we’re going to have to grapple with.

Josh Newby-Harpole Founder, Theresa Harpole Foundation for Metastatic Breast Cancer in Alton

We have a foundation we started this year in honor of my mom. She was diagnosed over seven years ago with stage zero breast cancer. They did genetic testing and found out she had the BRCA gene. In 2010 she got diagnosed with metastatic breast cancer after she had a lump in her neck and it had spread to her bones. I needed to get tested at that point. I had testing done in Chicago and found out that I had the BRCA gene. As a male I’m lucky she had a son and not a daughter. My mom has been on different courses of treatment, and I monitor my health as well as I can, because I have a higher risk for certain kinds of cancer such as prostate and skin cancer and a higher than 3 percent chance of breast cancer.

The cost was probably over $2,000 to have the test done, and I paid close to $1,000 for it. We’re very excited about the Supreme Court ruling. I think a lot of people are hesitant to get the test done because of the cost. It’s exciting because it means possibilities. More people are going to be motivated to do research in labs to try to find a cure. Maybe they can come up with better treatment options for women because some of them will find out they have the gene and they don’t have evidence of disease. It’s something that is really getting a lot of attention right now, and the population is maybe not as aware about things like BRCA and metastatic breast cancer.

Yvette Liebesman Assistant professor of law, St. Louis University

It’s very good for research and in fact it’s very good for health care in the sense that already today a competitor for Myriad said they would run the same test for thousands less. Already we’re seeing a good thing happening that more women are going to be able to be tested for this gene. Now we’re talking about more women being aware of their health risks. Now a company that wants to develop a drug isn’t going to have to go through Myriad to isolate this gene in order to test drugs for breast cancer.

If Myriad won this case it would be like saying while a tree is made by nature, if I find a way to pick the leaves off it, the leaf is my patented product. Myriad did win in one sense, that there is a form of DNA not found in nature that is patentable. This is very logical. I think that like with most things, the people who are doomsayers will say it’s not going to have as great of an impact. The idea that now this opens up the ability to develop treatments is going to be huge.

___ (c)2013 the St. Louis Post-Dispatch Visit the St. Louis Post-Dispatch at
www.stltoday.com Distributed by MCT Information Services

Georgina Gustin and Blythe Bernhard

SOURCE: Comtex

http://predictwallstreet.com/news/Story.aspx?StoryID=31159b4101f28d00

UPDATED 6/13/2013, following the new Supreme Court Decision on 6/13/2013 to include it, below.

By Robert Barnes, Updated: Thursday, June 13, 12:46 PM

http://www.washingtonpost.com/politics/supreme-court-rules-human-genes-may-not-be-patented/2013/06/13/9e5c55d2-d43d-11e2-a73e-826d299ff459_story.html?hpid=z1

The Supreme Court ruled unanimously Thursday that human genes cannot be patented, a decision that could shape the future of medical and genetic research and have profound effects on pharmaceuticals and agriculture.The ruling was a split decision for Myriad Genetics Inc., which holds patents on genes that have been linked to breast and ovarian cancer.

Justice Clarence Thomas, writing for the court, said that merely isolating those specific genes — called BRCA1 and BRCA2 — was not worthy of a patent.

“Myriad found the location of the BRCA1 and BRCA2 genes, but that discovery, by itself, does not render the BRCA genes . . . patent eligible,” Thomas wrote.On the other hand, Thomas wrote, Myriad’s creation of a synthetic form of DNA — called cDNA — based on its discovery does deserve patent protection.“The lab technician creates something new when cDNA is made,” Thomas wrote.Responding to the decision, Myriad focused on the favorable cDNA ruling. “We believe the court appropriately upheld our claims on cDNA, and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection for our BRACAnalysis test moving forward,” said Peter D. Meldrum, company president and chief executive. “More than 250,000 patients rely upon our BRACAnalysis test annually, and we remain focused on saving and improving peoples’ lives and lowering overall health-care costs.”DNA research is a vital component of personalized medicine. The challenge to Myriad’s patents came from scientists and doctors who said that allowing patents on genes inflated the cost of testing and hindered research.

The American Civil Liberties Union praised the high court’s ruling as a victory. “Today, the court struck down a major barrier to patient care and medical innovation,” said Sandra Park of the ACLU, which represented the groups that brought the challenge. “Because of this ruling, patients will have greater access to genetic testing, and scientists can engage in research on these genes without fear of being sued.”

The test that Myriad offers for determining whether a woman contains the genetic mutation that heightens her chance of cancer has received much attention lately after actress Angelina Jolie wrote about it in a letter to the editor to the New York Times. In the letter, Jolie revealed that she had a double mastectomy because the test showed she carried the defective gene.

http://www.washingtonpost.com/politics/supreme-court-rules-human-genes-may-not-be-patented/2013/06/13/9e5c55d2-d43d-11e2-a73e-826d299ff459_story.html?hpid=z1

[bold and green added by the Curator]

START QUOTE

1 (Slip Opinion) OCTOBER TERM, 2012

Syllabus

NOTE: Where it is feasible, a syllabus (headnote) will be released, as is being done in connection with this case, at the time the opinion is issued.The syllabus constitutes no part of the opinion of the Court but has been prepared by the Reporter of Decisions for the convenience of the reader. See United States v. Detroit Timber & Lumber Co., 200 U. S. 321, 337.

SUPREME COURT OF THE UNITED STATES

Syllabus

ASSOCIATION FOR MOLECULAR PATHOLOGY ET AL.

v. MYRIAD GENETICS, INC., ET AL.

CERTIORARI TO THE UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT

No. 12–398. Argued April 15, 2013—Decided June 13, 2013

Each human gene is encoded as deoxyribonucleic acid (DNA), which takes the shape of a “double helix.” Each “cross-bar” in that helix consists of two chemically joined nucleotides. Sequences of DNA nucleotides contain the information necessary to create strings of amino acids used to build proteins in the body. The nucleotides that code for amino acids are “exons,” and those that do not are “introns.” Scientists can extract DNA from cells to isolate specific segments for study. They can also synthetically create exons-only strands of nucleotides known as composite DNA (cDNA). cDNA contains only the exons that occur in DNA, omitting the intervening introns. Respondent Myriad Genetics, Inc. (Myriad), obtained several patents after discovering the precise location and sequence of the BRCA1 and BRCA2 genes, mutations of which can dramatically increase the risk of breast and ovarian cancer. This knowledge allowed Myriad to determine the genes’ typical nucleotide sequence, which, in turn, enabled it to develop medical tests useful for detecting mutations in these genes in a particular patient to assess the patient’s cancer risk. If valid, Myriad’s patents would give it the exclusiveright to isolate an individual’s BRCA1 and BRCA2 genes, and would give Myriad the exclusive right to synthetically create BRCA cDNA. Petitioners filed suit, seeking a declaration that Myriad’s patents areinvalid under 35 U. S. C. §101. As relevant here, the District Court granted summary judgment to petitioners, concluding that Myriad’s claims were invalid because they covered products of nature. The Federal Circuit initially reversed, but on remand in light of Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U. S. ___, the Circuit found both isolated DNA and cDNA patent eligible. 2 ASSOCIATION FOR MOLECULAR PATHOLOGY v. MYRIAD GENETICS, INC. Syllabus

Held: A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring. Pp. 10–18.

(a) The Patent Act permits patents to be issued to “[w]hoever invents or discovers any new and useful . . . composition of matter,” §101, but “laws of nature, natural phenomena, and abstract ideas”“ ‘are basic tools of scientific and technological work’ ” that lie beyond the domain of patent protection, Mayo, supra, at ___. The rule against patents on naturally occurring things has limits, however. Patent protection strikes a delicate balance between creating “incentives that lead to creation, invention, and discovery” and “imped[ing] the flow of information that might permit, indeed spur, invention.” Id., at ___. This standard is used to determine whether Myriad’s patents claim a “new and useful . . . composition of matter,” §101, or claim naturally occurring phenomena. Pp. 10–11.

(b) Myriad’s DNA claim falls within the law of nature exception.Myriad’s principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes. Diamond v. Chakrabarty, 447 U. S. 303, is central to the patent-eligibility inquiry whether such action was new “with markedly different characteristics from any found in nature,” id., at 310. Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA. It found an important and useful gene, but ground breaking, innovative, or even brilliant discovery does not by itself satisfy the §101 inquiry. See Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U. S. 127. Finding the location of the BRCA1 and BRCA2 genes does not render the genes patent eligible “new . . . composition[s] of matter,” §101. Myriad’s patent descriptions highlight the problem with its claims: They detail the extensive process of discovery, but extensive effort alone isinsufficient to satisfy §101’s demands. Myriad’s claims are not saved by the fact that isolating DNA from the human genome severs the chemical bonds that bind gene molecules together. The claims are not expressed in terms of chemical composition, nor do they rely on the chemical changes resulting from the isolation of a particular DNA section. Instead, they focus on the genetic information encoded in the BRCA1 and BRCA2 genes. Finally, Myriad argues that the Patent and Trademark Office’s past practice of awarding gene patents is entitled to deference, citing J. E. M. Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U. S. 124, a case where Congress had endorsed a PTO practice in subsequent legislation. There has been no such endorsement here, and the United States argued in the Federal Circuit and in this Court that isolated DNA was not patent eligible under §101. Pp. 12–16.

3 Cite as: 569 U. S. ____ (2013)

Syllabus

(c) cDNA is not a “product of nature,” so it is patent eligible under§101. cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments. Its creation results in an exons-only molecule, which is not naturally occurring. Its order of the exons may be dictated by nature, but the lab technician unquestionably creates something new when introns are removed from a DNA sequence to make cDNA. Pp. 16–17.

(d) This case, it is important to note, does not involve method claims, patents on new applications of knowledge about the BRCA1 and BRCA2 genes, or the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Pp. 17–18.

689 F. 3d 1303, affirmed in part and reversed in part.

THOMAS, J., delivered the opinion of the Court, in which ROBERTS, C. J., and KENNEDY, GINSBURG, BREYER, ALITO, SOTOMAYOR, and KAGAN, JJ., joined, and in which SCALIA, J., joined in part. SCALIA, J., filed an opinion concurring in part and concurring in the judgment.

1 Cite as: 569 U. S. ____ (2013) Opinion of SCALIA, J.

SUPREME COURT OF THE UNITED STATES

No. 12–398

ASSOCIATION FOR MOLECULAR PATHOLOGY, ET AL., PETITIONERS v. MYRIAD GENETICS, INC., ET AL.

ON WRIT OF CERTIORARI TO THE UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT

[June 13, 2013]

JUSTICE SCALIA, concurring in part and concurring in the judgment.

I join the judgment of the Court, and all of its opinion except Part I–A and some portions of the rest of the opinion going into fine details of molecular biology. I am un-able to affirm those details on my own knowledge or even my own belief. It suffices for me to affirm, having studied the opinions below and the expert briefs presented here, that the portion of DNA isolated from its natural state sought to be patented is identical to that portion of the DNA in its natural state; and that complementary DNA (cDNA) is a synthetic creation not normally present in nature.

END QUOTE

http://www.concurringopinions.com/archives/2013/06/the-humble-justice-scalia.html

Evolution of the case ASSOCIATION FOR MOLECULAR PATHOLOGY ET AL. v. MYRIAD GENETICS, INC., ET AL. priot to 6/13/2013 Supreme Court decision

Curator: Aviva Lev-Ari, PhD, RN

In an amicus brief, the Broad Institute‘s Eric Lander shares his personal view of the ongoing gene patenting case between Myriad Genetics and the American Civil Liberties Union, saying that isolated DNA fragments are products of Nature.

The central issue of the case revolves around Myriad’s patents on the BRCA1 and BRCA2 genes. In a mixed ruling, the federal appeals court found that while some of the company’s methods patents may not be patentable, its BRCA1 and BRCA2 gene patents, as they concern isolated DNA fragments, are patentable items as human intervention is needed to isolate DNA.

Lander argues that that is not true, though, as the Boston Globe points out, his brief was not filed in support of either side. Isolated DNA, he says, happens all the time in nature. “It is well-accepted in the scientific community that

(a) chromosomes are constantly being broken into DNA fragments by natural biological processes that break the covalent bonds within DNA chains;

(b) these DNA fragments can be routinely found in the human body … and

(c) these fragments cover the entire human genome and, in particular, include many of the DNA fragments claimed by Myriad’s patents,” the brief says.

The US Supreme Court announced in December that it will re-hear the Myriad gene patenting case.

SOURCE:

http://www.genomeweb.com//node/1197026?hq_e=el&hq_m=1513361&hq_l=1&hq_v=545fefd9ea

Eric Lander weighs in on gene patenting case

By Carolyn Y. Johnson

| GLOBE STAFF

FEBRUARY 26, 2013

Late last year, the nation’s highest court said it would consider a legal challenge to patents that biotechnology company Myriad Genetics holds on breast cancer genes. Now, Eric Lander, head of the Broad Institute in Cambridge, has filed an amicus brief that he says reflects his personal opinion. Utah-based Myriad, Lander argues, has patented products of nature, and its patents are an “insurmountable barrier” to studying DNA, with serious repercussions for medical progress.

http://bostonglobe.com/lifestyle/health-wellness/2013/02/26/eric-lander-human-genome-project-leader-weighs-supreme-court-gene-patenting-case/EjRae5IRYwUYRVLg6NXTZL/story.html

amicus brief

http://www.americanbar.org/content/dam/aba/publications/supreme_court_preview/briefs-v2/12-398_neither_amcu_lander.authcheckdam.pdf

In the Supreme Court of the United States – On Writ of Certiorari to the United States Court of Appeals for the Federal Circuit

The Association for Molecular Pathology, et al., v. Mariad Genetics, Inc, et al.,

Brief for Amicus Curiae Eric S. Lander in support of neither party

SCIENTIFIC CITATIONS

Eric S. Lander et al., Initial Sequencing and Analysis of the Human Genome, 409 Nature 860 (2001)

Eric S. Lander, Initial Impact of the Sequencing of the Human Genome, 470 Nature 187 (2011)

ARGUMENT

1. THE FEDERAL CIRCUIT INCORRECTLY ASSUMED, WITHOUT CITING SCIENTIFIC EVIDENCE, THAT ISOLATED DNA FRAGMENTS OF THE HUMAN GENOME DO NOT OCCUR IN NATURE, WHEN IT IS WELL-ACCEPTED IN THE SCIENTIFIC COMMUNITY THAT THEY DO

2. MYRIAD’S COMPOSITION-OF-MATTER CLAIMS ON ISOLATED FRAGMENTS OF THE GENOMIC DNA ARE INCONSISTENT WITH THIS COURT’S SECTION 101 JURISPRUDENCE BECAUSE THEY (1) ARE DIRECTED TO PREEXISTING PRODUCTS OF NATURE (2) EXCLUDE OTHERS FROM OBSERVING, CHARACTERIZING OR ANALYZING THESE PRODUCTS OF NATURE BY ANY MEANS WHATSOEVER; AND (3) CREATE AN INSURMOUNTABLE BARRIER TO SCIENTIFIC PROGRESS AND TECHNOLOGICAL INNOVATION CONCERNING THESE PRODUCTS OF NATURE

3. A NARROWLY CRAFTED DECISION BY THIS COURT WOULD NOT UNDERMINE THE BIOTECHNOLOGY INDUSTRY AND INSTEAD WOULD FOSTER INNOVATION

CONCLUSION

It is well-accepted in the scientific community that isolated DNA fragments of the human genome – including isolated DNA fragments of the BRCA1 and BRCA2 genes – are found routinely in th human body and are thus patent-ineligible products of Nature. The biotechnology industry would not be substantially affected by a narrowly crafted decision here holding that

1) fragments of human genome DNA are patent-ineligible where the claimed molecules themselves are routinely found in Nature and where the process for purification or synthesis of such molecules iS routine and

(2) cDNAs are patent-eligible.

http://www.americanbar.org/content/dam/aba/publications/supreme_court_preview/briefs-v2/12-398_neither_amcu_lander.authcheckdam.pdf

Susan McBee and Bryan Jones Guest

Posted Thu, February 7th, 2013 10:16 am

The Supreme Court should be mindful of naturally derived products other than nucleic acids when deciding Myriad

The following contribution to our gene patenting symposium come from Susan McBee and Bryan Jones. Ms. McBee is the Chair of the Life Sciences Intellectual Property Team for Baker, Donelson, Bearman, Caldwell, and Berkowitz, P.C. Bryan Jones is a registered patent attorney in the Washington D.C. office of Baker, Donelson, Bearman, Caldwell, and Berkowitz, P.C.

In April, the Supreme Court will hear oral argument in Association for Molecular Pathology v. Myriad, ostensibly on the question whether so-called “gene patents” satisfy 35 U.S.C. § 101. However, Myriad is about more than whether “genes” can be patented. It is about what types of activities justify patent protection. Does one need to create something that is unlike anything else that has ever existed in order to justify a patent? Or is it enough to discover something that was previously unknown, remove it from its natural environment, and show that it has a practical application?

This is a critical question to the biotechnology industry, because many biotechnological products are not novel chemical structures, but naturally occurring products. Between 1981 and 2006, approximately forty percent of all pharmaceuticals approved for use by the FDA were a biologic, natural product, or derived from a natural product. Moreover, for start-up biotechnology companies, patents covering such products are incredibly important, “as they are often the most crucial asset they own in a sector that is extremely research-intensive and with low imitation costs.” Strong and enforceable patents to these core products therefore are vitally important to the healthy development of the biotechnology industry.

Before the Myriad case, the Court has not had an opportunity to consider the patentability of such products. Therefore, this case has the potential to have an enormous impact on the viability of the business model in this industry.

In Myriad, Judge Lourie and Judge Moore both found “isolated” nucleic acids to be patentable, but for different reasons. Judge Lourie was convinced that isolated nucleic acids are patentable because isolation “breaks covalent bonds” relative to the longer native nucleic acid, thereby resulting in a new chemical entity. Judge Moore reasoned that, if analyzed on a blank slate, she would require the product to have a “substantial new utility” relative to its natural function in order to satisfy 35 U.S.C. § 101. While we agree that the generation of a novel chemical entity or demonstration of a new utility would be sufficient to satisfy 35 U.S.C. § 101, we do not believe these to be necessary requirements.

Consider, for example, Taq polymerase. The inclusion of Taq into a process called polymerase chain reaction (PCR) has often been credited as being the single most important technological advance to the modern biotechnology industry. PCR uses repeated cycles of increasing and decreasing temperatures in the presence of a polymerase to amplify a target nucleic acid. In the original iteration of PCR, new polymerase enzyme had to be added to the reaction mixture after each heat cycle, because the high temperature permanently deactivated the enzyme. Taq, however, is heat stable and thus does not lose activity when subjected to high temperatures. Because of this stability, Taq only needs to be added to a PCR reaction mixture once, thus greatly reducing the costs and the time of performing the process, and permitting easy automation. Clearly, then, the identification and characterization of this enzyme is a significant technological advance, from which the public obtains a significant benefit. Yet the properties of Taq that make it so attractive for PCR are a consequence of its structure and function in the natural world. Taq is naturally produced by Thermus aquaticus, a bacterium that is naturally found in hot springs. Therefore, in nature, just like in PCR, Taq functions as a thermostable enzyme that catalyzes the amplification of a nucleic acid. Why should this render Taq unpatentable?

The Constitution does not require a claimed compound to have a formally “new” chemical structure or new function to justify a patent. Article I, section 8 of the Constitution authorizes patents “[t]o promote the Progress of Science and useful Arts . . . .” As explained by the Court:

Congress may not authorize the issuance of patents whose effects are to remove existent knowledge from the public domain, or to restrict free access to materials already available. Innovation, advancement, and things which add to the sum of useful knowledge are inherent requisites in a patent system which by constitutional command must ‘promote the Progress of useful Arts.’ This is the standard expressed in the Constitution and it may not be ignored.

Thus, the Constitution only limits patents that “remove existent knowledge from the public domain” or “restrict free access to materials already available.” Assuming that Taq was not previously known, a claim to it in isolated form simply cannot “remove existent knowledge from the public domain.” Because Taq naturally exists only in the context of a living organism, claiming it in “isolated” form cannot “restrict free access to” its source. Thus, constitutional limits cannot justify a prohibition on patents covering isolated naturally occurring products.

Nor does 35 U.S.C. § 101 clearly prohibit such patents. The statute specifically encompasses “discoveries,” so long as those discoveries relate to processes, compositions of matter, or articles of manufacture that are “new” and “useful.” In most cases, naturally occurring products are found in very minute quantities in complex association with other molecules inside living organisms. The act of isolating the natural product removes them from this context, thereby inevitably resulting in a composition that is materially different than anything that exists in nature. An “isolated” natural product therefore is “new” compared to the same product in its natural state. Its discovery thus could justify a claim under 35 U.S.C. § 101.

Finally, Supreme Court precedent does not clearly prohibit patenting of such claims. Under the closest Supreme Court precedent, a patent that is limited to a “non-naturally occurring article of manufacture or composition of matter” satisfies 35 U.S.C. § 101. Although it is often convenient to describe naturally occurring compounds in terms of chemical structure or nucleotide or amino acid sequence, they rarely if ever exist in nature as isolated compositions. Rather, they are found in complex associations with other compositions, usually within living organisms. The removal of these products from their natural context sometimes results in distinct chemical entities, such as the isolated nucleic acids in Myriad. Other times, the result is a highly purified form of the compound, such as isolated adrenaline or purified vitamin B12. In each case, however, the intervention of man is required to produce the “isolated” composition. Claims directed to “isolated” natural compounds thus are limited to purely artificial, non-naturally occurring compositions of matter. This should make them patentable, irrespective of whether they have a novel chemical structure or new utility in isolated form.

It is our sincere hope that the Court will not only find isolated nucleic acids to be patentable, but that it will do so under a rationale which allows for other naturally derived products to similarly be patentable. In as much as a possible test can be garnered, our recommendation is to find that a naturally derived product satisfies 35 U.S.C. § 101 as long as it is claimed in a purely man-made form (and thus is “new”), and the form in which it is claimed has a practical utility disclosed in the Specification (and thus is “useful”). This test closely aligns with the plain language of 35 U.S.C. § 101. Challenges to the eligibility of such claims could then focus on two clear issues: (1) whether the claim encompasses the product in its natural state; and (2) whether the claim is reasonably commensurate in scope with the disclosed utility (i.e., is the claim narrowly tailored to products that possess the disclosed utility?). This allows overly broad claims to be invalidated without resorting to a categorical ban on a broad class of subject matter. Moreover, it would not require courts to answer the philosophical question of whether something has enough of a structural or functional change to justify a patent.

Posted in Association for Molecular Pathology v. Myriad Genetics, Featured, Gene Patenting Symposium

Recommended Citation: Susan McBee and Bryan Jones, The Supreme Court should be mindful of naturally derived products other than nucleic acids when deciding Myriad, SCOTUSblog (Feb. 7, 2013, 10:16 AM), http://www.scotusblog.com/2013/02/the-supreme-court-should-be-mindful-of-naturally-derived-products-other-than-nucleic-acids-when-deciding-myriad/

– See more at: http://www.scotusblog.com/?p=159001#sthash.UGzQgi2x.dpuf

Appeals Court Affirms Isolated DNA Patents in Myriad Case

August 16, 2012

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A federal appeals court today has for a second time reversed a lower district court’s decision that isolated genes are not patentable, but it also partly affirmed the District Court’s decision that certain methods patents “comparing” or “analyzing” gene sequences may not be patentable.

The Supreme Court recently asked the US Court of Appeals for the Federal Circuit to reconsider its earlier decision in the case, The Association for Molecular Pathology v. the US Patent and Trademark Office and Myriad Genetics, in light of its ruling in another lawsuit, called Mayo Collaborative Services v. Prometheus Laboratories.

AMP v USPTO focuses on the patentability of Myriad Genetics’ claims on isolated gene sequences and diagnostic methods related to its BRACAnalysis test. In Mayo v Prometheus, the Supreme Court recently invalidated patents held by diagnostics firm Prometheus because they merely described laws of nature, and did not apply those laws of nature in a markedly different manner as to warrant a patent.

Despite the Supreme Court’s ruling in Mayo, the CAFC in a 2-1 decision maintained that although isolated gene sequences may be derived from naturally occurring substances, their isolation requires human intervention in order to make them useful in medical care and so are deserving of patent protection.

“We are very pleased with the favorable decision the Court rendered today which again confirmed that isolated DNA is patentable,” Myriad Genetics President and CEO Peter Meldrum said in a statement. “Importantly, the court agreed with Myriad that isolated DNA is a new chemical matter with important utilities which can only exist as the product of human ingenuity.”

The decision was met with disappointment by those opposing gene patenting.

“It is extremely disappointing that despite the Supreme Court’s ruling, the appeals court has failed to fully re-consider the facts of this case,” Chris Hansen, a staff attorney with the ACLU Speech, Privacy and Technology Project, said in a statement.

The case against Myriad was filed in 2009 by the Public Patent Foundation, American Civil Liberties Union, AMP, and others who claim that patents cannot cover natural phenomena and that Myriad’s patents, and others like them, will hinder genetics research and keep some people from accessing tests and second opinions.

“This ruling prevents doctors and scientists from exchanging their ideas and research freely,” Hansen added the ACLU statement today. “Human DNA is a natural entity like air or water. It does not belong to any one company.”

Myriad said again today what it has argued all along, that gene patents have not thwarted research, that the cost of its BRACAnalysis test is not prohibitive and is covered through most insurance for “appropriate” patients, and that second opinion testing is available in many US labs.

“Certainly, you could hear a collective sigh of relief from the biotech industry, as of this decision,” Jennifer Camacho, an attorney and shareholder with law firm Greenberg Traurig, told GenomeWeb Daily News today.

“Isolated DNA patents remain intact. We still have patent eligibility for isolated DNA,” Camacho said, explaining that the court’s decision to uphold the patentability of isolated DNA may be seen by the biotech industry as more important than its reading of the reach of the Prometheus decision.

“They did actually take [the Prometheus decision] into consideration,” Camacho said, adding that it did not change the judges’ analysis.

“This puts a narrow interpretation of Prometheus in the books, as being limited to the ‘laws of nature’ exclusion, she added.

Camacho told GWDN that she was struck by how similar today’s CAFC ruling was to the original. She pointed out that part of one judge’s opinion, which argued that whether some patents should or should not be awarded are policy questions that are best left to Congress, was the same language as in the first opinion.

For Myriad, the ruling provided mixed results, Goldman Sachs Investment Research analyst Isaac Ro said in a note today.

On the positive side for Myriad, the patent eligibility of its BRCA1 and BRCA2-based tests was upheld again based on its isolated DNA claims and screening method claims. But a potential negative is that the CAFC also upheld the District Court’s opinion that Myriad’s method claims for comparing DNA sequences are not eligible.

“The outcome is modestly disappointing,” Ro stated, adding that the critical question now is whether or not the Supreme Court will agree to hear the case next year.

US Supreme Court Agrees to Hear Myriad Patent Case Again

NEW YORK (GenomeWeb News) – The US Supreme Court decided on Friday to once again hear the American Civil Liberty Union’s case against Myriad Genetics challenging the firm’s patent rights related to BRCA1 and BRCA2 genes.

The decision by the court to hear the case — originally filed by ACLU, the Public Patent Foundation, the Association for Molecular Pathology and others in 2009 — comes a little more than three months after a federal appeals courtissued a mixed ruling in which it found that isolated genes are patentable, but that certain methods patents that compare or analyze gene sequences may not be.

The US Court of Appeals for the Federal Circuit issued its decision in August after the Supreme Court asked it in March to reconsider a decision rendered by the appeals court in 2011 in light of the Supreme Court’s decision in another case, Mayo Collaborative Services v. Prometheus Laboratories. In that case, the Supreme Courtinvalidated patents held by Prometheus, saying the patents merely described laws of nature but did not apply those laws of nature in a markedly different manner as to warrant a patent.

The appeals court originally ruled in July 2011 that Myriad’s patents covering isolated DNA are patentable under Section 101 of the US Patent Act, reversing a decision by the Federal District Court for the Southern District of New York that isolated DNA is not much different from gene sequences found in nature and therefore is not patentable.

This past September, ACLU and the Public Patent Foundation asked the Supreme Court to once again take up the issue of whether Myriad’s claims on genes that predict the risk of ovarian and breast cancer can be patented. ACLU and the foundation contend that Myriad’s BRCA1 and BRCA2 gene patents should be invalidated because the genes are products of nature and allowing Myriad patent protection stifles scientific research and patient access to medical care.

“Myriad did not invent human genes, and has no right to claim ownership of them just because they removed them from the body,” Daniel Ravicher, executive director of PUBPAT, said in a statement on Friday. “The government does not have the right to give a corporation the exclusive power to control what we know about our own genetic makeup.”

Myriad President and CEO Peter Meldrum said in a statement, however, that patent protection is necessary to drive technological innovation.

“Two previous decisions by the Federal Circuit Court of Appeals confirmed the patentability of our groundbreaking diagnostic test that has helped close to 1 million people learn about their hereditary cancer risk,” he said. “Myriad devoted more than 17 years and $500 million to develop its BRACAnalysis test. The discovery and development of pioneering diagnostics and therapeutics require a huge investment and our US patent system is the engine that drives this innovation.

“This case has great importance for the hundreds of millions of patients whose lives are saved and enhanced by the life science industry’s products,” he said.

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Curator: Aviva Lev-Ari, PhD, RN

Thymosin beta 4 (Tβ4)

Recently,

Tβ4 was shown to be expressed in the developing heart and found to stimulate migration of cardiomyocytes and endothelial cells, promote survival of cardiomyocytes (Nature, 2004), and most recently
to play an essential role in all key stages of cardiac vessel development: vasculogenesis, angiogenesis, and arteriogenesis (Nature 2006).

These results suggest that Tβ4 may have significant therapeutic potential in humans to protect myocardium and promote cardiomyocyte survival in the acute stages of ischemic heart disease.

SOURCE:

http://onlinelibrary.wiley.com/doi/10.1196/annals.1415.051/abstract;jsessionid=BB7CC897572B7DDB60370EA64A81FC3F.d01t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false

EXPLORATIONS with THYMOSIN beta4 FOR INDUCING ADULT EPICARDIAL PROGENETOR MOBILIZATION AND NEOVASCULARIZATION is presented in

Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

http://pharmaceuticalintelligence.com/2012/04/30/93/

Clinical Study Data of Thymosin beta 4 Presented

Published on October 3, 2009 at 5:10 AM

Myocardial Development of RGN-352 (Injectable Tβ4 Peptide)

David Crockford, RegeneRx’s vice president for clinical and regulatory affairs presented an overview of the biological properties that support Tβ4’s near term and long term clinical applications. Mr. Crockford noted that special emphasis is being placed on the development of RGN-352 for the systemic (injectable) treatment of patients with ST-elevation myocardial infarction (STEMI) in combination with percutaneous coronary intervention, the current standard of care in most western countries for this common type of heart attack. The goal with RGN-352 is to prevent or repair continued damage to cardiac tissue post-heart attack, when such tissue around the damaged site remains at risk.

Dr. Dennis Ruff, vice president and medical director of ICON, and principal investigator, presented the most current results on the Phase I safety study with RGN-352 entitled, “A Randomized, Double-blind, Placebo-controlled, Dose-response Phase I Study of the Safety and Tolerability of the Intravenous Administration of Thymosin Beta 4 and its Pharmacokinetics After Single and Multiple Doses in Healthy Volunteers.” Dr. Ruff discussed key aspects of the study and concluded with, “There were no dose limiting or serious adverse events throughout the dosing period. Synthetic Tβ4 administered intravenously up to 1260 mg, and for up to 14 days, appears to be well tolerated with low incidence of adverse events and no evidence of serious adverse events.”

http://www.news-medical.net/news/20091003/Clinical-study-data-of-Thymosin-beta-4-presented.aspx

RegeneRx Receives Notice of Allowance from Chinese Patent Office for Treatment and Prevention of Heart Disease

RegeneRx Receives Notice of Allowance from Chinese Patent Office for Treatment and Prevention of Heart Disease

February 7, 2013 — Rockville, Md.

http://www.regenerx.com/wt/page/pr_1360265259

Active Research on Thymosins in Cardiovascular Disease Reported in 2010 and 2012 Annual Conference on Thymosins, Proceedings by NY Academy of Sciences

Use of the cardioprotectants thymosin β4 and dexrazoxane during congenital heart surgery: proposal for a randomized, double-blind, clinical trial

Neonates and infants undergoing heart surgery with cardioplegic arrest experience both inflammation and myocardial ischemia-reperfusion (IR) injury. These processes provoke myocardial apoptosis and oxygen-free radical formation that result in cardiac injury and dysfunction. Thymosin β4 (Tβ4) is a naturally occurring peptide that has cardioprotective and antiapoptotic effects. Similarly, dexrazoxane provides cardioprotection by reduction of toxic reactive oxygen species (ROS) and suppression of apoptosis. We propose a pilot pharmacokinetic/safety trial of Tβ4 and dexrazoxane in children less than one year of age, followed by a randomized, double-blind, clinical trial of Tβ4 or dexrazoxane versus placebo during congenital heart surgery. We will evaluate postoperative time to resolution of organ failure, development of low cardiac output syndrome, length of cardiac ICU and hospital stays, and echocardiographic indices of cardiac dysfunction. Results could establish the clinical utility of Tβ4 and/or dexrazoxane in ameliorating ischemia-reperfusion injury during congenital heart surgery.[1]

Cardiac repair with thymosin β4 and cardiac reprogramming factors

Heart disease is a leading cause of death in newborns and in adults. We previously reported that the G-actin–sequestering peptide thymosin β4 promotes myocardial survival in hypoxia and promotes neoangiogenesis, resulting in cardiac repair after injury. More recently, we showed that reprogramming of cardiac fibroblasts to cardiomyocyte-like cells in vivo after coronary artery ligation using three cardiac transcription factors (Gata4/Mef2c/Tbx5) offers an alternative approach to regenerate heart muscle. We have combined the delivery of thymosin β4 and the cardiac reprogramming factors to further enhance the degree of cardiac repair and improvement in cardiac function after myocardial infarction. These findings suggest that thymosin β4 and cardiac reprogramming technology may synergistically limit damage to the heart and promote cardiac regeneration through the stimulation of endogenous cells within the heart.[2]

NMR structural studies of thymosin α1 and β-thymosins

Thymosin proteins, originally isolated from fractionation of thymus tissue, represent a class of compounds that we now know are present in numerous other tissues, are unrelated to each other in a genetic sense, and appear to have different functions within the cell. Thymosin α1 (generic drug name thymalfasin; trade name Zadaxin) is derived from a precursor molecule, prothymosin, by proteolytic cleavage, and stimulates the immune system. Although the peptide is natively unstructured in aqueous solution, the helical structure has been observed in the presence of trifluoroethanol or unilamellar vesicles, and these studies are consistent with the presence of a dynamic helical structure whose sides are not completely hydrophilic or hydrophobic. This helical structure may occur in circulation when the peptide comes into contact with membranes. In this report, we discuss the current knowledge of the thymosin α1 structure and similar properties of thymosin β4 and thymosin β9, in different environments.[3]

Thymosin β4 sustained release from poly (lactide-co-glycolide) microspheres: synthesis and implications for treatment of myocardial ischemia

A sustained release formulation for the therapeutic peptide thymosin β4 (Tβ4) that can be localized to the heart and reduce the concentration and frequency of dose is being explored as a means to improve its delivery in humans. This review contains concepts involved in the delivery of peptides to the heart and the synthesis of polymer microspheres for the sustained release of peptides, including Tβ4. Initial results of poly(lactic-co-glycolic acid) microspheres synthesized with specific tolerances for intramyocardial injection that demonstrate the encapsulation and release of Tβ4 from double-emulsion microspheres are also presented.[4]

Thymosin β4 and cardiac repair

Hypoxic heart disease is a predominant cause of disability and death worldwide. As adult mammals are incapable of cardiac repair after infarction, the discovery of effective methods to achieve myocardial and vascular regeneration is crucial. Efforts to use stem cells to repopulate damaged tissue are currently limited by technical considerations and restricted cell potential. We discovered that the small, secreted peptide thymosin β4 (Tβ4) could be sufficiently used to inhibit myocardial cell death, stimulate vessel growth, and activate endogenous cardiac progenitors by reminding the adult heart on its embryonic program in vivo. The initiation of epicardial thickening accompanied by increase of myocardial and epicardial progenitors with or without infarction indicate that the reactivation process is independent of injury. Our results demonstrate Tβ4 to be the first known molecule able to initiate simultaneous myocardial and vascular regeneration after systemic administration in vivo. Given our findings, the utility of Tβ4 to heal cardiac injury may hold promise and warrant further investigation.[7]

Thymosin β4 facilitates epicardial neovascularization of the injured adult heart

Ischemic heart disease complicated by coronary artery occlusion causes myocardial infarction (MI), which is the major cause of morbidity and mortality in humans (http://www.who.int/cardiovascular_diseases/resources/atlas/en/index.html). After MI the human heart has an impaired capacity to regenerate and, despite the high prevalence of cardiovascular disease worldwide, there is currently only limited insight into how to stimulate repair of the injured adult heart from its component parts. Efficient cardiac regeneration requires the replacement of lost cardiomyocytes, formation of new coronary blood vessels, and appropriate modulation of inflammation to prevent maladaptive remodeling, fibrosis/scarring, and consequent cardiac dysfunction. Here we show that thymosin β4 (Tβ4) promotes new vasculature in both the intact and injured mammalian heart. We demonstrate that limited EPDC-derived endothelial-restricted neovascularization constitutes suboptimal “endogenous repair,” following injury, which is significantly augmented by Tβ4 to increase and stabilize the vascular plexus via collateral vessel growth. As such, we identify Tβ4 as a facilitator of cardiac neovascularization and highlight adult EPDCs as resident progenitors which, when instructed by Tβ4, have the capacity to sustain the myocardium after ischemic damage.[8]

Thymosin β4 enhances repair by organizing connective tissue and preventing the appearance of myofibroblasts

Incisional wounds in rats treated locally with thymosin β4 (Tβ4) healed with minimal scaring and without loss in wound breaking strength. Treated wounds were significantly narrower in width. Polarized light microscopy treated wounds had superior organized collagen fibers, displaying a red birefringence, which is consistent with mature connective tissue. Control incisions had randomly organized collagen fibers, displaying green birefringence that is consistent with immature connective tissue. Immunohistology treated wounds had few myofibroblasts and fibroblasts with α smooth muscle actin (SMA) stained stress fibers. Polyvinyl alcohol sponge implants placed in subcutaneous pockets received either carrier or 100 μg of Tβ4 on days 2, 3, and 4. On day 14, treated implants revealed longer, thicker collagen fiber bundles with intense yellow-red birefringence by polarized light microscopy. In controls, fine, thin collagen fiber bundles were arranged in random arrays with predominantly green birefringence. Controls contained mostly myofibroblasts, while few myofibroblasts appeared in Tβ4 treated implants. Electron microscopy confirmed both cell types and the degree of collagen fiber bundle organization. Our results demonstrate that Tβ4 treated wounds appear to mature earlier and heal with minimal scaring.[9]

Thymosin β4: a key factor for protective effects of eEPCs in acute and chronic ischemia

Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI-3K/Akt-dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre-treatment with thymosin β4 shRNA was performed. Thymosin ß4 peptide retroinfusion mimicked the eEPC-derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin ß4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin ß4 dependent manner. [10]

Thymosin β4: a candidate for treatment of stroke?

Neurorestorative therapy is the next frontier in the treatment of stroke. An expanding body of evidence supports the theory that after stroke, certain cellular changes occur that resemble early stages of development. Increased expression of developmental proteins in the area bordering the infarct suggest an active repair or reconditioning response to ischemic injury. Neurorestorative therapy targets parenchymal cells (neurons, oligodendrocytes, astrocyes, and endothelial cells) to enhance endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis to promote functional recovery. Pharmacological treatments include statins, phosphodiesterase 5 inhibitors, erythropoietin, and nitric oxide donors that have all improved funtional outcome after stroke in the preclinial arena. Thymosin β4 (Tβ4) is expressed in both the developing and adult brain and it has been shown to stimulate vasculogenesis, angiogenesis, and arteriogenesis in the postnatal and adult murine cardiac myocardium. In this manuscript, we describe our rationale and techniques to test our hypothesis that Tβ4 may be a candidate neurorestorative agent. [11]

Prothymosin α as robustness molecule against ischemic stress to brain and retina

Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions, including memory, sensory perception, and motor skills. As necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. We identified the nuclear protein, prothymosin alpha (ProTα) from the conditioned medium of serum-free culture of cortical neurons as a key protein-inhibiting necrosis. In the culture of cortical neurons in the serum-free condition without any supplements, ProTα inhibited the necrosis, but caused apoptosis. In the ischemic brain or retina, ProTα showed a potent inhibition of both necrosis and apoptosis. By use of anti-brain-derived neurotrophic factor or anti-erythropoietin IgG, we found that ProTα inhibits necrosis, but causes apoptosis, which is in turn inhibited by ProTα-induced neurotrophins under the condition of ischemia. From the experiment using anti-ProTα IgG or antisense oligonucleotide for ProTα, it was revealed that ProTα has a pathophysiological role in protecting neurons in stroke.[12]

Thymosin β4 and cardiac repair

Thymosin β4 facilitates epicardial neovascularization of the injured adult heart

schemic heart disease complicated by coronary artery occlusion causes myocardial infarction (MI), which is the major cause of morbidity and mortality in humans (http://www.who.int/cardiovascular_diseases/resources/atlas/en/index.html). After MI the human heart has an impaired capacity to regenerate and, despite the high prevalence of cardiovascular disease worldwide, there is currently only limited insight into how to stimulate repair of the injured adult heart from its component parts. Efficient cardiac regeneration requires the replacement of lost cardiomyocytes, formation of new coronary blood vessels, and appropriate modulation of inflammation to prevent maladaptive remodeling, fibrosis/scarring, and consequent cardiac dysfunction. Here we show that thymosin β4 (Tβ4) promotes new vasculature in both the intact and injured mammalian heart. We demonstrate that limited EPDC-derived endothelial-restricted neovascularization constitutes suboptimal “endogenous repair,” following injury, which is significantly augmented by Tβ4 to increase and stabilize the vascular plexus via collateral vessel growth. As such, we identify Tβ4 as a facilitator of cardiac neovascularization and highlight adult EPDCs as resident progenitors which, when instructed by Tβ4, have the capacity to sustain the myocardium after ischemic damage. [14]

Thymosin β4: a key factor for protective effects of eEPCs in acute and chronic ischemia

Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI-3K/Akt-dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre-treatment with thymosin β4 shRNA was performed. Thymosin ß4 peptide retroinfusion mimicked the eEPC-derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin ß4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin ß4 dependent manner.[15]

Thymosin β4: a candidate for treatment of stroke?

Thymosin β4: structure, function, and biological properties supporting current and future clinical applications

Published studies have described a number of physiological properties and cellular functions of thymosin β4 (Tβ4), the major G-actin-sequestering molecule in mammalian cells. Those activities include the promotion of cell migration, blood vessel formation, cell survival, stem cell differentiation, the modulation of cytokines, chemokines, and specific proteases, the upregulation of matrix molecules and gene expression, and the downregulation of a major nuclear transcription factor. Such properties have provided the scientific rationale for a number of ongoing and planned dermal, corneal, cardiac clinical trials evaluating the tissue protective, regenerative and repair potential of Tβ4, and direction for future clinical applications in the treatment of diseases of the central nervous system, lung inflammatory disease, and sepsis. A special emphasis is placed on the development of Tβ4 in the treatment of patients with ST elevation myocardial infarction in combination with percutaneous coronary intervention.[17]

The effect of thymosin treatment of venous ulcers

Venous ulcers are responsible for about 70% of the chronic ulcers of the lower limbs. Standard of care includes compression, dressings, debridement of devitalized tissue, and infection control. Thymosin beta 4 (Tβ4), a synthetic copy of the naturally occurring 43 amino-acid peptide, has been found to have wound healing and anti-inflammatory properties, and is thought to exert its therapeutic effect through promotion of keratinocyte and endothelial cell migration, increased collagen deposition, and stimulation of angiogenesis. To assess the safety, tolerability, and efficacy of topically administered Tβ4 in patients with venous stasis ulcers, a double-blind, placebo-controlled, dose-escalation study was conducted in eight European sites (five in Italy and three in Poland) that enrolled and randomized 73 patients. The safety profile of all doses of administered Tβ4 was deemed acceptable and comparable to placebo. Efficacy findings from this Phase 2 study suggest that a Tβ4 dose of 0.03% may have the potential to accelerate wound healing and that complete wound healing can be achieved within 3 months in about 25% of the patients, especially among those whose wounds are small to moderate in size or mild to moderate in severity.[18]

A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin β4 in healthy volunteers

Synthetic thymosin beta 4 (Tβ4) may have a potential use in promoting myocardial cell survival during acute myocardial infarction. Four cohorts, with 10 healthy subjects each, were given a single intravenous dose of placebo or synthetic Tβ4. Cohorts received ascending doses of either 42, 140, 420, or 1260 mg. Following safety review, subjects were given the same dose regimen daily for 14 days. Safety evaluations, incidence of Treatment-Emergent Adverse Events, and pharmacokinetic parameters were evaluated. Adverse events were infrequent, and mild or moderate in intensity. There were no dose limiting toxicities or serious adverse events. Pharmacokinetic profile for single dose showed a dose proportional response, and an increasing half-life with increasing dose. Synthetic Tβ4 given intravenously as a single dose or in multiple daily doses for 14 days over a dose range of 42–1260 mg was well tolerated with no evidence of dose limiting toxicity. Further development for use in cardiac ischemia should be considered.[19]

Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction

+Author Affiliations

¹University of California, San Diego, La Jolla, CA 92093, USA.
²Ventrix, Inc., San Diego, CA 92109, USA.
³Biologics Delivery Systems, Irwindale, CA 91706, USA.
⁴Barrow Neurological Institute, Phoenix, AZ 85013, USA.

+Author Notes

↵* These authors contributed equally to this work.

↵†To whom correspondence should be addressed. E-mail: christman@eng.ucsd.edu

http://stm.sciencemag.org/content/5/173/173ra25?elq=72fb0aad78aa4423b81b5d5943a30532

Sci Transl Med 20 February 2013:
Vol. 5, Issue 173, p. 173ra25

ABSTRACT

New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix as a scaffold for cardiac repair after MI. We establish the safety and efficacy of this injectable biomaterial in large- and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel 2 weeks after MI and evaluated after 3 months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.

Citation: S. B. Seif-Naraghi, J. M. Singelyn, M. A. Salvatore, K. G. Osborn, J. J. Wang, U. Sampat, O. L. Kwan, G. M. Strachan, J. Wong, P. J. Schup-Magoffin, R. L. Braden, K. Bartels, J. A. DeQuach, M. Preul, A. M. Kinsey, A. N. DeMaria, N. Dib, K. L. Christman, Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction.

Sci. Transl. Med. 5, 173ra25 (2013).

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RESEARCH ARTICLE:BIOMEDICAL ENGINEERING Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair
- Yi-Dong Lin,
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- Ying-Chang Hsueh,
- Min-Yao Chang,
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REFERENCES OF THYMOSIN IN CARDIOVASCULAR DISEASE

Thymosins in Health and Disease II: 3^rd International Symposium on The Emerging Clinical Applications of Tymosin beta 4 in Cardiovascular Disease

Annals of the New York Academy of Sciences, October 2012 Volume 1270 Pages vii-ix, 1–121.

Allan L. Goldstein, Enrico Garaci, Editors, Thymosins in Cardiovascular Disease, November 2012, Wiley-Blackwell

http://onlinelibrary.wiley.com/doi/10.1111/nyas.2012.1270.issue-1/issuetoc

http://www.wiley.com/WileyCDA/WileyTitle/productCd-1573319104.html?cid=RSS_WILEY2_LIFEMED

1   Use of the cardioprotectants thymosin β4 and dexrazoxane during congenital heart surgery: proposal for a randomized, double-blind, clinical trial (pages 59–65) Daniel Stromberg, Tia Raymond, David Samuel, David Crockford, William Stigall, Steven Leonard, Eric Mendeloff and Andrew Gormley Article first published online: 10 OCT 2012 | DOI: 10.1111/j.1749-6632.2012.06710.x

2   Cardiac repair with thymosin β4 and cardiac reprogramming factors (pages 66–72) Deepak Srivastava, Masaki Ieda, Jidong Fu and Li Qian Article first published online: 10 OCT 2012 | DOI: 10.1111/j.1749-6632.2012.06696.x

3 NMR structural studies of thymosin α1 and β-thymosins (pages 73–78) David E. Volk, Cynthia W. Tuthill, Miguel-Angel Elizondo-Riojas and David G. Gorenstein Article first published online: 10 OCT 2012 | DOI: 10.1111/j.1749-6632.2012.06656.x

4  Thymosin β4 sustained release from poly(lactide-co-glycolide) microspheres: synthesis and implications for treatment of myocardial ischemia (pages 112–119) Jeffrey E. Thatcher, Tré Welch, Robert C. Eberhart, Zoltan A. Schelly and J. Michael DiMaio Article first published online: 10 OCT 2012 | DOI: 10.1111/j.1749-6632.2012.06681.x

5 Corrigendum for Ann. N.Y. Acad. Sci. 2012. 1254: 57–65 (page 121) Article first published online: 10 OCT 2012 | DOI: 10.1111/j.1749-6632.2012.06793.x This article corrects: A bird’s-eye view of cell therapy and tissue engineering for cardiac regeneration Vol. 1254, Issue 1, 57–65, Article first published online: 30 APR 2012

Thymosins in Health and Disease: 2nd International Symposium,
Annals of the New York Academy of Sciences, May 2010 Volume 1194 Pages ix–xi, 1–230

http://onlinelibrary.wiley.com/doi/10.1111/nyas.2010.1194.issue-1/issuetoc

6. Preface to Thymosins in Health and Disease (pages ix–xi) Enrico Garaci and Allan L. Goldstein Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05493.x

7. Thymosin β4 and cardiac repair (pages 87–96) Santwana Shrivastava, Deepak Srivastava, Eric N. Olson, J. Michael DiMaio and Ildiko Bock-Marquette Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05468.x

8. Thymosin β4 facilitates epicardial neovascularization of the injured adult heart (pages 97–104) Nicola Smart, Catherine A. Risebro, James E. Clark, Elisabeth Ehler, Lucile Miquerol, Alex Rossdeutsch, Michael S. Marber and Paul R. Riley Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05478.x

9. Thymosin β4 enhances repair by organizing connective tissue and preventing the appearance of myofibroblasts (pages 118–124) H. Paul Ehrlich and Sprague W. Hazard III Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05483.x

10. Thymosin β4: a key factor for protective effects of eEPCs in acute and chronic ischemia (pages 105–111) Rabea Hinkel, Ildiko Bock-Marquette, Antonis K. Hazopoulos and Christian Kupatt Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05489.x Corrected by: Corrigendum for Ann. N. Y. Acad. Sci. 1194: 105–111 Vol. 1205, Issue 1, 284, Article first published online: 14 SEP 2010

11.  Thymosin β4: a candidate for treatment of stroke? (pages 112–117) Daniel C. Morris, Michael Chopp, Li Zhang and Zheng G. Zhang Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05469.x

12. Prothymosin α as robustness molecule against ischemic stress to brain and retina (pages 20–26) Hiroshi Ueda, Hayato Matsunaga, Hitoshi Uchida and Mutsumi Ueda Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05466.x

13. Thymosin β4 and cardiac repair (pages 87–96) Santwana Shrivastava, Deepak Srivastava, Eric N. Olson, J. Michael DiMaio and Ildiko Bock-Marquette Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05468.x

14.  Thymosin β4 facilitates epicardial neovascularization of the injured adult heart (pages 97–104) Nicola Smart, Catherine A. Risebro, James E. Clark, Elisabeth Ehler, Lucile Miquerol, Alex Rossdeutsch, Michael S. Marber and Paul R. Riley Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05478.x

15.  Thymosin β4: a key factor for protective effects of eEPCs in acute and chronic ischemia (pages 105–111) Rabea Hinkel, Ildiko Bock-Marquette, Antonis K. Hazopoulos and Christian Kupatt Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05489.x Corrected by: Corrigendum for Ann. N. Y. Acad. Sci. 1194: 105–111 Vol. 1205, Issue 1, 284, Article first published online: 14 SEP 2010

16.  Thymosin β4: a candidate for treatment of stroke? (pages 112–117) Daniel C. Morris, Michael Chopp, Li Zhang and Zheng G. Zhang Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05469.x

17.Thymosin β4: structure, function, and biological properties supporting current and future clinical applications (pages 179–189) David Crockford, Nabila Turjman, Christian Allan and Janet Angel Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05492.x

18.  The effect of thymosin treatment of venous ulcers (pages 207–212) G. Guarnera, A. DeRosa and R. Camerini, on behalf of 8 European sites Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05490.x

19. A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin β4 in healthy volunteers (pages 223–229) Dennis Ruff, David Crockford, Gino Girardi and Yuxin Zhang Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05474.x

Thymosin References

Posted in Acute Myocardial Infarction, Frontiers in Cardiology and Cardiovascular Disorders, Heart Failure (HF), Origins of Cardiovascular Disease, Resident-cell-based on February 27, 2013| Leave a Comment »

Thymosin References

Reporter: Aviva Lev-Ari, PhD, RN

http://onlinelibrary.wiley.com/doi/10.1111/nyas.2012.1270.issue-1/issuetoc

Annals of the New York Academy of Sciences

Volume 1194 Thymosins in Health and Disease: 2nd International Symposium

Pages ix–xi, 1–230, May 2010

http://www.wiley.com/WileyCDA/WileyTitle/productCd-1573319104.html?cid=RSS_WILEY2_LIFEMED

http://onlinelibrary.wiley.com/doi/10.1111/nyas.2010.1194.issue-1/issuetoc

6. Preface to Thymosins in Health and Disease (pages ix–xi) Enrico Garaci and Allan L. Goldstein Article first published online: 3 MAY 2010 | DOI: 10.1111/j.1749-6632.2010.05493.x

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Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Posted in Alzheimer's Disease, BioSimilars, Etiology, Human Immune System in Health and in Disease, Pharmacotherapy and Cell Activity, Systemic Inflammatory Response Related Disorders, tagged Alzheimer, Alzheimers Disease, Beta amyloid, Interleukin 12 on February 27, 2013| 1 Comment »

Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 4/1/2022

on clinicaltrials.gov

Study NCT02835716
Submitted Date: September 10, 2016 (v3)

Study Identification


Unique Protocol ID:	PCD=OO ALZ
Brief Title:	Pre-Clinical (Alzheimers) Diagnosis PCD = Optimum Outcomes OO (PCD=OOALZ)
Official Title:	Pre-Clinical Alzheimer’s (ALZ) Diagnosis (PCD) = Optimum Outcomes (OO)

https://clinicaltrials.gov/ct2/history/NCT02835716?V_3=View

one of our articles used as a reference for this clinical trial entry

see below

Links:

URL: http://print.ispub.com/api/0/ispub-article/7521

Description: Multidimensional Representation of Concepts as Cognitive Engrams in the Human Brain

URL: http://ispub.com/IJH/8/1/9567

Description: Evaluation of Cognitive Impairment

URL: https://pharmaceuticalintelligence.com/2013/02/27/ustekinumab-new-drug-therapy-for-cognitive-decline-resulting-from-neuroinflammatory-cytokine-signaling-and-alzheimers-disease/

Description: Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease–like pathology and cognitive decline

These authors contributed equally to this work.
- Johannes vom Berg &
- Stefan Prokop

Affiliations

Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Johannes vom Berg,
- Florian Mair &
- Burkhard Becher
Department of Neuropathology, Charité–Universitätsmedizin Berlin, Berlin, Germany.
- Stefan Prokop,
- Kelly R Miller,
- Juliane Obst,
- Roland E Kälin,
- Ileana Lopategui-Cabezas,
- Anja Wegner,
- Carola G Schipke &
- Frank L Heppner
Department of Psychiatry, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
- Carola G Schipke &
- Oliver Peters
Cognitive Neurobiology and Berlin Mouse Clinic for Neurology and Psychiatry, Humboldt University, Berlin, Germany.
- York Winter
Present address: Institute of Basic and Preclinical Sciences ‘Victoria de Girón’, Medical University of Havana, Havana, Cuba.
- Ileana Lopategui-Cabezas
These authors jointly directed this work.
- Burkhard Becher &
- Frank L Heppner

Abstract

The pathology of Alzheimer’s disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using theAPPPS1 Alzheimer’s disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer’s disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer’s disease pathology and cognitive deficits.

Nature Medicine 18, 1812–1819 (2012) doi:10.1038/nm.2965, Published online 25 November 2012

Psoriasis Drug Fights Alzheimer’s By Treating It Like An Auto-Immune Disease

by Elizabeth Nolan Brown

One of the primary culprits in the neurobiological development of Alzheimer’s disease is a protein called amyloid beta, which can build up and form plaques in the brain. Now European scientists are reporting that a common psoriasis drug could stop these plaques from forming by targeting a natural inflammatory response in our brains — lending credence to the idea of Alzheimer’s as an auto-immune disease.

In a study published this week in the journal Nature Medicine, Swedish and German researchers say a medication already widely in use to treat plaque psoriasis was able to slow the accumuation of amyloid plaques in the brains of mice, as well as improve brain functioning in older mice that already had Alzheimer’s disease.

The drug, ustekinumab, works by suppressing the brain’s immune response to the amyloid-beta protein. Its effectiveness lends support to the idea of Alzheimer’s disease as an auto-immune disease similar to type-2 diabetes, spurred at least in part by the bodies response to inflammation.

The study authors urged the U.S. Food & Drug Administration should approve ustekinumab for patients with early Alzheimer’s disease or mild cognitive impairment and said drugs that shut down specific immune responses — like those used in psoriasis, Crohn’s disease and multiple sclerosis — are “the ideal candidate for the initiation of clinical trials” for Alzheimer’s.

That’s very good news, because pharmaceutical companies have been ready to give up on Alzheimer’s drug development after so many of the drugs being tested for the past decade or more have been failures. Most of those drugs worked under different theories of treating Alzheimer’s disease, focusing more on things like busting up existing plaques or treating the external symptoms of Alzheimer’s.

http://www.blisstree.com/2012/11/28/sex-relationships/psoriasis-drug-fights-alzheimers-by-treating-it-like-an-auto-immune-disease/#ixzz2M7ceuApw

Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

W. Sue T. Griffin, Ph.D.

N Engl J Med 2013; 368:770-771 February 21, 2013, DOI: 10.1056/NEJMcibr1214546

Immune events may influence development and progression of Alzheimer’s disease. In a mouse model, mice depleted of p40, a cytokine subunit, showed reduced cerebral amyloidosis. Administration of anti-p40 antibodies reduced levels of soluble β-amyloid and restored some cognitive function.

Inflamatory events and AD

http://www.nejm.org/doi/full/10.1056/NEJMcibr1214546

Neuroinflammation, expressed as frank microglial activation with excessive expression of immune cytokines, is fast acquiring the status of “principal culprit” in the unresolved connection between an elevated risk for the development of

sporadic Alzheimer’s disease and
traumatic brain injury,
systemic infections,
normal aging, and
several neurologic disorders.

Neuroinflammation also appears to be a substantial contributor to Alzheimer’s disease in persons with Down’s syndrome (owing to the excess gene dosage that is characteristic of the syndrome) and in persons with genetic mutations that affect the amyloid precursor protein (APP) or presenilin.1 The molecules and pathways that mediate the inflammation associated with Alzheimer’s disease have recently come under scrutiny. An advance in this area has been described by Vom Berg et al.,2 who used a mouse model of Alzheimer’s disease to investigate the role of proinflammatory cytokines in disease pathogenesis.

Their results show that damping the expression and signaling of the cytokines interleukin-12 and interleukin-23 in the mouse model is associated with decreases in microglial activation, in the level of soluble β-amyloid (Aβ), and in the overall Aβ plaque burden. These findings are consistent with earlier studies that linked microglial activation with excess expression of interleukin-1 (which regulates interleukin-12–interleukin-23 signaling3) and expression of APP (which when cleaved generates Aβ), the development of Aβ plaques, and the activation of microglia in the brains of patients with Alzheimer’s disease.

Vom Berg et al. also observed that intracerebroventricular delivery of an antibody against p40 — a subunit common to both interleukin-12 and interleukin-23 — reversed the age-related cognitive decline in mice and that this reversal was accompanied by a reduction in levels of soluble Aβ. These observations suggest that the suppression of signaling by interleukin-12, interleukin- 23, or other inflammatory cytokines may prevent or delay the onset of Alzheimer’s disease and, for patients already undergoing the cognitive decline of Alzheimer’s disease, may halt such decline.

These findings raise the question of whether monoclonal p40 antibodies (ustekinumab and briakinumab), which have already been approved by the Food and Drug Administration for the treatment of psoriasis, should be tested in randomized, controlled trials for the treatment of Alzheimer’s disease. Also of interest is a large epidemiologic study4 in which the rate of incident Alzheimer’s disease decreased by almost 50% among persons who took the common nonsteroidal antiinflammatory agent (NSAID) ibuprofen for 5 years, a finding that suggests that experimental investigation of NSAIDs as preventive agents is warranted.

Given the mounting sociological, economic, and personal costs of Alzheimer’s disease, the lack of a perfect understanding of its mechanisms should not stop researchers from conducting clinical studies of a variety of strategies intended to reduce the risk of development of the disease and of experimental approaches to expedite its treatment.

W. Sue T. Griffin, Ph.D.: Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Donald W. Reynolds Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, and the Geriatric Research, Education, and Clinical Center (GRECC) at the Central Arkansas Veterans Healthcare System — both in Little Rock.

1. Griffin WS, Barger SW. Neuroinflammatory cytokines — the common thread in Alzheimer’s pathogenesis. US Neurol 2010; 6(2):19-27.

2. Vom Berg J, Prokop S, Miller KR, et al. Inhibition of IL-12/ IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 2012;18:1812-9.

3. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13: 715-25.

4. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008;70:1672-7.

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Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Posted in Atherogenic Processes & Pathology, Biological Networks, Biomarkers & Medical Diagnostics, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Myocardial Metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, Translational Research, Translational Science, tagged Aviva Lev-Ari, Children's Hospital Boston, DNA, DNA Sequencing, genetics, Harvard Medical School, Human Genome Project, Illumina, Partners HealthCare, Personalized medicine on February 25, 2013| 3 Comments »

Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 5/4/2015

Goes to Clinic @MGH: Clinically validated versions of Exome Sequencing and Analysis using Broad-developed methods like Hybrid Capture, the Genome Analysis Toolkit (GATK), and MuTect

http://pharmaceuticalintelligence.com/2015/05/04/goes-to-clinic-mgh-clinically-validated-versions-of-exome-sequencing-and-analysis-using-broad-developed-methods-like-hybrid-capture-the-genome-analysis-toolkit-gatk-and-mutect/

Center for Personalized Genetic Medicine, Partners HealthCare and Harvard Medical School

The Partners HealthCare Center for Personalized Genetic Medicine offers technologies and technical support for the research activities of Partners investigators. Our objective is to help investigators advance their research programs and to provide the highest quality service, technical expertise, and leading technologies for genomics research. Our goal is to broaden the access to these technologies while offering the best customer service in the most cost conscious and time efficient manner possible.

We are organized into four principal service areas:

sequence analysis,
genotyping,
expression analysis, and
bioprocessing/sample management

Our platforms include next generation sequencing with Illumina HiSeq2000 and GA ii analyzers as well as Sanger sequencing using ABI 3730 XL sequence analyzers. Targeted custom genotyping is offered using Sequenom and Illumina GoldenGate panels as well as GWAS scale projects using Illumina Infinium and DNA methylation analysis using Illumina bead arrays. Expression analysis is available with capabilities for processing total RNA on either Affymetrix or Illumina arrays.

Through services from our BioSample Services Facility (BSF) and Partners Biorepository for Medical Discovery (PBMD) teams we provide a research platform for handling samples in a standardized manner to provide consistency from sample to sample. The BSF is able to assist investigators to configure projects utilizing your own samples or coupled with the PCPGM-PBMD we are able to support the integration of cohorts of samples selected from the PBMD into analysis on our genomics platforms.

http://pcpgm.partners.org/research-services

DNA Sequencing

The DNA Sequencing Group at the Partners HealthCare Center for Personalized Genetic Medicine has a strong history of producing high quality, dependable, and informative results for collaborators and clients. The DNA Sequencing Group participated in the Human Genome Project, building the STS-Based BAC map for Human Chromosome 12, and providing Chromosome 12 tiling path clones to the Baylor Human Genome Sequencing Center for sequencing.

The group sequenced 113 BACs for the Mouse Genome Project, contributing 24 megabases of finished mouse sequences to the published Mouse Genome, as well as providing draft sequences for unique strains of several bacterial genomes, including Pseudomonas aeruginosa, and Vibrio cholerae. More recently, the group participated in identifying mutations linked to numerous diseases, either in collaborations or by providing client laboratories with full service resequencing and analysis.

Services by Project Goals

Mutation Identification via Resequencing

This facility provides full-service resequencing of regions of interest in one or more genomic DNAs, including the following:

Discussion of the scope of the project and a cost quote
Identification of genes in the region of interest as needed, with the Investigator
Primer design using our automated system, to amplify desired regions
Primer ordering
QC of the primers on DNA standards, if required
PCR amplification of DNA provided by Investigator
PCR clean-up
Sequencing reactions
Sequencing reaction clean-up
Sequence application to the ABI 3730 XL Analyzer
Chromatograms are made available to Investigator over web (GIGPAD)
Data assembly and analysis using Phred Phrap and PolyPhred
One round of repeats and redesign if necessary
Report of variations found throughout sequence
Trouble shooting for 100% coverage if desired

Research Services

Fee-for-service sequencing
Fragment analysis / genotyping (Microsatellite Instability)

Technology Development

New technology testing and development
Collaborative Protocol development
Beta-test site for instrumentation and software

Clinical Diagnosis

Diagnostic test development
Sequencing for clinical diagnostics group

Genomic Sequencing Projects

Human
Rodent
Bacteria

http://pcpgm.partners.org/research-services/sequencing

Advancing Translational Genomics through Personalized Medicine Projects

The mission of the Partners HealthCare Center for Personalized Genetic Medicine (PCPGM) is to utilize genetics and genomics to promote and implement personalized medicine in caring for patients throughout the Partners HealthCare system and in health care nationally and globally.

The Personalized Medicine Project program was developed to support the clinical research efforts of junior Partners HealthCare investigators for translational genetics and genomic projects to advance personalized medicine. The goal of this program is to identify biological markers that can be used as potential predictive tests. This will be accomplished by:

Leveraging the Partners HealthCare Research Patient Data Registry (RPDR) and the Partners Biorepository for Medical Discovery (PBMD), centralized locations where Partners HealthCare patient data and/or samples are stored.
Identifying novel biological markers or new uses for existing markers.
Focusing on tests that could:
- improve diagnostic sensitivity or specificity;
- further stratify patient groups with a given diagnosis;
- predict improved clinical outcomes; or
- assist with selection of therapies or methods to manage disease.

http://pcpgm.partners.org/biorepository/pmprojectsrfp

Harvard Medical School Genetics Training Program

The Harvard Medical School (HMS) Genetics Training Program is one of the oldest and largest programs in the country. It was founded by Drs. John Littlefield at the Massachusetts General Hospital and Park Gerald at Children’s Hospital Boston in the early 1970’s. The program has trained scientists and clinicians who have become leaders in academic genetics, and has supported investigators who have made major contributions to the clinical practice of genetics and genetics research.

The HMS Genetics Training Program is accredited by the ABMG in all areas of training – Clinical Genetics, Biochemical Genetics, Cytogenetics, and Molecular Genetics. This provides an opportunity for our trainees to become active candidates for board certification in a discipline(s) of medical genetics in addition to receiving laboratory training. The training laboratories and clinics of the program are centered at HMS and its affiliated institutions including Brigham and Women’s Hospital (BWH), the HMS Department of Genetics, Beth Israel Deaconess Medical Center (BIDMC), Children’s Hospital Boston (CHB), Dana Farber Cancer Institute (DFCI), and Massachusetts General Hospital (MGH). The HMS Genetics Training Program provides trainees the opportunity to take advantage of the extraordinarily rich academic environment offered at HMS and its affiliated institutions as well as the greater Boston scientific community.

http://pcpgm.partners.org/educational-programs/harvard-medical-school-genetics-training-program

Cardiovascular Research Center @MGH

The Cardiovascular Research Center was founded in 1990, and occupies over 30,000 sq. ft. of laboratory space in both the Charlestown Navy Yard and the Richard B. Simches Research Building. Dr. Mark Fishman, now president of the Novartis Institutes for Biomedical Research, directed the Center from 1990 until 2002. From 2002-2005, Dr. Kenneth Bloch served as Interim Director and then in June 2005, the Massachusetts General Hospital welcomed Dr. Kenneth Chien as the new scientific director of the Cardiovascular Research Center. Prior to his MGH appointments, Dr. Chien directed the Institute for Molecular Medicine at the University of California at San Diego. An internationally recognized biologist specializing in cardiovascular science, he is a true pioneer in developing new therapeutic strategies to prevent the onset and progression of heart failure. Dr. Chien served as director until 2012.

Cardiovascular Research Center investigators have made many groundbreaking discoveries. Among these include:

• first identification of progenitor cells in the heart
• cloning of the first vertebrate cell death genes
• knocking out the genes that produce nitric oxide (NO), showing the importance of this molecule to atherosclerosis and stroke
• clinical use of NO to treat patients with pulmonary hypertension
• development of gene and cell transfer approaches to treat heart failure
• performance of the first large-scale genetic screen in a vertebrate (the zebrafish)
• identification of genes critical to cardiac pacemaking, rhythm, contractile function, and normal heart patterning
• discovery of a new methylase gene responsible for altering DNA structure during an individual’s lifetime

The Cardiovascular Research Center has taken great pride in the training of scientists with MDs and/or PhDs, as well as graduate students from a variety of Boston area institutions.

The Cardiovascular Research Center has two locations, one in the Charlestown Navy Yard and the other on the main campus’s Charles River Plaza complex in the Richard Simches Research Center.

Both the Simches and Navy Yard sites offer state of the art facilities, including tissue culture rooms, warm and cold rooms, histology rooms, autoclave facilities, hot labs, scope rooms and conference rooms. The Navy Yard lab has a topnotch zebrafish facility that is utilized by many scientists both inside and outside the Center, and a transgenic mouse core for both knock-ins and knock-outs. The Navy Yard facilities also contain echocardiogram equipment, specialized microscopes equipped with video capability for making movies, as well as a confocal microscope available to the Center researchers. The Simches lab houses the CVRC Stem Cell Biology + Therapy program, including a dedicated facility for human ES cell based technology, run by Dr. Chad Cowan, and future plans for high throughput screening facility to allow chemical screening in ESX cell based systems. Other cores available to researchers include a Cell Sorting and Flow Cytometry lab and a DNA sequencing core.

The Cardiology Laboratory for Integrative Physiology & Imaging lab is dedicated to large animal studies. An in house interventional cardiologist specializing in large animals performs the surgeries. In addition there are technicians that assist in the daily operations of the lab and can assist in experiment design and project implementation. This lab specializes in large animal imaging, CAT scans and catheter base manipulations. There is also an MRI imaging facility housed in the lab.

http://www2.massgeneral.org/cvrc/about.html

Genomics and Cardiovascular Medicine @MGH

	Translational Medicine: Genomics and Proteomics @MGH

The goal of the Translational Medicine Program is to harness the rich clinical cardiovascular population at the Massachusetts General Hospital to identify and validate novel genomic determinants of cardiovascular disease. Our goal is not to capture the entire cohort of cardiovascular patients presenting to Massachusetts General Hospital, but rather to focus our efforts on extremely well-phenotyped human models that are unique to cardiovascular disease. Of particular interest are “perturbational” studies in humans (e.g., cardiac exercise testing) that elicit robust phenotypes in affected individuals to serve as the springboard for analyses that span from genomics to proteomics and biochemical profiling. The Translational Medicine Program will involve a multidisciplinary group of investigators who contribute expertise in cardiovascular basic science, clinical cardiology, genetic/genomic epidemiology, bioinformatics, imaging, pathology, as well as clinical chemistry and mass spectrometry. While the Program in Translational Medicine will be physically located at the Massachusetts General Hospital Main Campus, the effort will leverage ongoing interdisciplinary collaborations with investigators at the Framingham Heart Study, the Broad Institute of M.I.T., Harvard University, and Harvard Medical School. Our goals are to:• Identify specific unmet needs in cardiovascular biomarker and pathway discovery (e.g., genomic markers of subclinical premature coronary artery disease, serum biomarkers of myocardial ischemia)• Match cutting-edge technologies with our unique patient cohorts for “first in man” studies• Establish the infrastructure necessary to phenotype patients with the targeted condition (from plasma samples, RNA, DNA, imaging, etc.) and enroll sufficiently sized cohort(s) with the requisite power to validate novel biomarkers.• Establish scientifically high priority research projects to target for independent funding.• Ultimately, develop novel therapeutic interventions.While efforts in translational investigation are already underway, this program will identify synergies between ongoing studies and catalyze new opportunities. Several of the ongoing projects that are anticipated to serve as cornerstones of this effort include:Proteomics and Metabolomics Studies (PI: Gerszten , Wang) Recent advances in proteomic and metabolic profiling technologies have enhanced the feasibility of high throughput patient screening for the diagnosis of disease states. Small biochemicals and proteins are the end result of the entire chain of regulatory changes that occur in response to physiological stressors, disease processes, or drug therapy. In addition to serving as biomarkers, both circulating metabolites and proteins participate as regulatory signals, such as in the control of blood pressure. Our ongoing studies have helped pioneer the application of novel mass spectrometry and liquid chromatography techniques to plasma analysis. In parallel with the profiling efforts, we have developed statistical software for functional pathway trend analysis and used it to demonstrate significant coordinate changes in specific pathways. Such analysis allows us to gain insight into the functionally relevant cellular mechanisms contributing to disease pathways and increases the likelihood that prospective biomarkers will be validated in other patient cohorts. Support for this effort would be synergistic with ongoing funding, including the recent appointment and support for Dr. Gerszten to lead a metabolomics initiative at the Broad Institute.Cardiovascular Genetics and Genomics Studies (PIs: Kathiresan, Newton-Cheh,Wang, and O’Donnell) Through the Human Genome Project and the International Haplotype Map project, researchers now have available the complete human genome sequence, a nearly complete set of common single nucleotide polymorphisms (SNPs), and a map of the patterns of correlation (“linkage disequilibrium”) among SNPs. Research on a large-scale is now possible to define associations of common, complex human cardiovascular diseases —such as myocardial infarction and sudden cardiac death—with genetic variants using candidate gene and genome-wide association studies, gene sequencing, and family-based linkage studies. Specific diseases and traits being studied by CVRC researchers include early-onset myocardial infarction, sudden cardiac death, blood lipids, blood pressure, electrocardiographic QT interval and blood hemostatic factor levels. These studies draw clinical material from the Massachusetts General Hospital and from collaborations with population-based epidemiologic cohorts such as the Framingham Heart Study. Like the metabolomics/proteomics work, these efforts build on the technologic and scientific expertise at the Broad Institute. Specifically, CVRC researchers leverage the Broad Institute’s expertise in large-scale genotyping, genomics, and statistical genetics. The collaboration between the Massachusetts General Hospital, the Framingham Heart Study, and the Broad Institute brings together resources that are unique to each institution to identify genes related to complex cardiovascular traits and to ultimately impact human health.Chemical Biology Program (PIs: Peterson and Shaw) Dr. Peterson’s group has championed the zebrafish as a tool for drug discovery. The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which large, phenotype-based screens can be performed. Because of these attributes, the zebrafish also provides opportunities to accelerate the process of drug discovery. By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish promises to contribute to several aspects of the drug development process, including target identification, disease modeling, lead discovery and toxicology. The Program in Translational Medicine will specifically support efforts to test novel pro-angiogenic factors (discovered as suppressors of the “gridlock” phenotype in zebrafish) on human cells such as circulating endothelial precursors.Dr. Shaw’s group is studying the cellular effects of human disease mutations in patient samples, by perturbing cells with a panel of thousands of drugs, and asking whether mutant versus wild-type cells react differently to a given biochemical (reminiscent of a genetic interaction screen). Dr. Shaw has demonstrated the feasibility of this approach using lymphoblast cell lines from a family affected by a monogenic form of diabetes (MODY1), and shown that glucocorticoid signaling differs between affected vs. unaffected patients. Because his studies incorporate the use of FDA-approved drugs, he can quickly identify both potentially “druggable” disease pathways as well as novel therapeutic agents. Further validation of these efforts in other monogenic disorders, such as LDL-receptor deficient patients is planned next. Ultimately this work will be extended to studies in complex genetic diseases.Director: Rob Gerszten, MDPrincipal Investigators: • Farouc Jaffer, MD, PhD • Sekar Kathiresan, MD • Chris Newton-Cheh, MD, MPH • Randall Peterson, PhD • Stanley Shaw, MD, PhD • Thomas Wang, MD

Genetic Basis of Cardiomyopathy

Original gene identification for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant

McNally E, MacLeod H, Dellefave L. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant. 2005 Apr 18 [Updated 2009 Oct 13]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.

Summary

Disease characteristics. Autosomal dominant arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Available from:

http://www.ncbi.nlm.nih.gov/books/NBK1131/

Pan Cardiomyopathy Panel

@the Center for Personalized Genetic Medicine of Partners HealthCare and Harvard Medical School

The Pan Cardiomyopathy (PCM) Panel contains 51 cardiomyopathy genes including Titin (TTN), which encodes the largest human protein. This panel covers genes associated with HCM, DCM, RCM, LVNC, ARVC and CPVT and uses a combination of Next Generation Sequencing technology and conventional Sanger sequencing.

For illustrative reference, click to see one of our images or diagrams. Genes on Pan Cardiomyopathy Panels, Disease-Gene Associations, Gene Cellular Location.

Please select on the disease to read more: HCM,DCM, ARVC/CPVT, or LVNC.

Current Tests:

Pan Cardiomyopathy Panel – 51 genes

HCM Panel – 18 genes^§
DCM Panel – 27 genes^§
ARVC/CPVT Panel – 8 genes^§
LVNC Panel – 10 genes^§

^§Optional reflex to remaining genes

Storage Cardiomyopathy – please select a disease to learn more

Unexplained Hypertrophy Panel (LAMP2 & PRKAG2)
Fabry Disease – GLA Gene Sequencing
Transthyretin Amyloidosis – TTR Gene Sequencing

For any other single gene tests, please call the LMM at 617-768-8499 or lmm@partners.org.

For Variant Classification Rules – Lab for Molecular Medicine (LMM)

http://pcpgm.partners.org/sites/default/files/LMM/Resources/LMM_VariantClassification_05.26.11.pdf

For LMM Reference Sequences

http://pcpgm.partners.org/sites/default/files/LMM/Resources/LMMRefSeq-2.20.13.pdf

When to order which panel?

The Pan Cardiomyopathy panel may shorten the “testing odyssey” when a clear diagnosis has not been established. However, because many genes have not yet been associated with more than one cardiomyopathy, interpretation of novel variants may be more difficult when they are found in a gene that is not (yet) known to cause the patient’s cardiomyopathy. Please note: We are expecting an increase in “variants of unknown significance” and recommend careful consideration of the following factors when deciding whether to order the full panel or the disease specific sub-panels. The Pan Cardiomyopathy Panel may be best suited for patients who have already exhausted current testing options or whose clinical diagnosis is not yet clear. It may also be a good first line test for patients who have a family history where the number of living affected relatives would allow segregation analysis to establish or rule out pathogenicity for “variants of unknown significance (VUSs)”. Finally, the patient’s personal preferences should be considered as VUSs can cause anxiety.

Disease Backgrounds

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) in a non-dilated ventricle. With a prevalence estimated to be ~1/500 in the general population, HCM is the most common monogenic cardiac disorder. To date, over 1000 variants have been identified in genes causative of HCM, most of which affect the sarcomere, the contractile unit of the cardiac muscle. In addition, defects in genes involved in storage diseases, such as LAMP2, PRKAG2 and GLA, typically cause systemic disease but may also result in predominant cardiac manifestations, which can mimic hypertrophic cardiomyopathy (HCM). For additional information about HCM, please visit GeneReviews.

Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. The estimated prevalence of DCM is 1/2,500 and about 20-35% of cases have a family history showing a predominantly autosomal mode of inheritance. To date, over 40 genes have been demonstrated to cause DCM, encoding proteins involved in the sarcomere, Z-disk, nuclear lamina, intermediate filaments and the dystrophin-associated glycoprotein complex. Variants in some genes cause additional abnormalities: LMNA variants are frequently found in DCM that occurs with progressive conduction system disease. Variants in the TAZ gene cause Barth syndrome, an X-linked cardioskeletal myopathy in infants. In addition, variants in several genes (including LMNA, DES, SGCD, TCAP and EMD) can cause DCM in conjunction with skeletal myopathy. For additional information about DCM, please visit GeneReviews.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is estimated to affect approximately 1/5,000 individuals in the general population, about half of which have a family history. The disease is characterized by replacement of myocytes by fatty or fibrofatty tissue, mainly in the right ventricle. The resulting manifestations are broad and include ventricular tachyarrhythmias and sudden death in young individuals and athletes. ARVC is typically inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity and to date, 5 ARVC genes (DSP, DSC2, DSG2, PKP2, TMEM43) have been identified, all but one (TMEM43) encode components of the desmosome. For more information about ARVC, please visit GeneReviews.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is typically characterized by exercise induced syncope due to ventricular tachycardia in individuals without structural heart disease. Two CPVT genes are known to date (RYR2 – autosomal dominant; CASQ2 – autosomal recessive). For more information about CPVT, please visit GeneReviews.

Left ventricular noncompaction (LVNC) has recently been established as a specific type of cardiomyopathy and is characterized by a spongy appearance of the left ventricular myocardium, resulting from an arrest in normal cardiac development. LVNC can be found in isolation or in association with other cardiomyopathies (HCM, DCM) as well as congenital cardiac abnormalities. The population prevalence is not known but LVNC is reported in ~0.014% of echocardiograms. LVNC is often familial and the genetic spectrum is beginning to emerge although it is not yet well defined. LVNC genes reported to date include ACTC, DTNA, LDB3, MYBPC3, MYH7, TAZ, and TNNT2 (Montserrat 2007, Klaassen 2008; Kaneda 2007, Zaragoza 2007; reviewed in: Maron 2006, Finsterer 2009). For more information about LVNC, please visit OMIM.org.

For any additional information, please contact us at 617-768-8500 or lmm@partners.org.

SOURCE:

http://pcpgm.partners.org/lmm/tests/cardiomyopathy

Genes: 51 genesMethodology: A combination of next generation sequencing technology and Sanger sequencingAnalytical Sensitivity:Substitutions: 100% (95%CI=98.5-100)Small InDels: 95% (95%CI=83-99)Clinical Sensitivity: See below.Additional Links:

Genetic Basis of Cardiomyopathy Booklet http://pcpgm.partners.org/sites/default/files/LMM/Resources/LMM_Cardiomyopathy_Booklet_2011.pdf

Cardiomyopathy

	Price	TAT	CPT Codes
Pan Cardiomyopathy Panel (51 Genes) – lmPCM-pnlAv2_L
	$3,950	8-12 wks	81479
HCM Panel (18 Genes) – lmPCM-pnlB_L
	$3,200	8-12 wks	81479
DCM Panel (27 Genes) – lmPCM-pnlCv2_L
	$3,850	8-12 wks	81479
ARVC/CPVT Panel (8 Genes) – lmPCM-pnlD_L
	$3,000	8-12 wks	81479
LVNC Panel (10 Genes) – lmPCM-pnlE_L
	$3,200	8-12 wks	81479
Remaining Pan Cardiomyopathy Genes (HCM Reflex) – lmPCM-pnlFv2_L
	$2,000	8-12 wks	81479
Remaining Pan Cardiomyopathy Genes (DCM Reflex) – lmPCM-pnlGv2_L
	$2,000	8-12 wks	81479
Remaining Pan Cardiomyopathy Genes (ARVC/CPVT Reflex) – lmPCM-pnlHv2_L
	$2,000	8-12 wks	81479
Remaining Pan Cardiomyopathy Genes (LVNC Reflex) – lmPCM-pnlIv2_L
	$2,000	8-12 wks	81479
Remaining Pan Cardiomyopathy Genes (Version 1 Reflex) – lmPCM-pnlL_L
	$750	8-12 wks	81479
Unexplained Cardiac Hypertrophy Panel (2 genes) – lmUCH-pnlA_L
	$1,500	3 wks	81479
ABCC9 Gene Sequencing – lmABCC9-a_L
	$1,800	3 wks	81479
ACTC Gene Sequencing – lmACTC-a_L
	$700	3 wks	81405
ACTN2 Gene Sequencing – lmACTN2-a_L
	$1,500	3 wks	81479
CSRP3 Gene Sequencing – lmCSRP3-a_L
	$900	3 wks	81479
CTF1 Gene Sequencing – lmCTF1-a_L
	$800	3 wks	81479
DES Gene Sequencing – lmDES-a_L
	$750	3 wks	81479
DSC2 Gene Sequencing – lmDSC2-a_L
	$1,150	3 wks	81479
DSG2 Gene Sequencing – lmDSG2-a_L
	$1,075	3 wks	81479
DSP Gene Sequencing – lmDSP-a_L
	$1,700	3 wks	81479
DTNA Gene Sequencing – lmDTNA-a_L
	$1,500	5-6 wks	81479
EMD Gene Sequencing – lmEMD-a_L
	$450	3 wks	81479
GLA Gene Sequencing – lmGLA-a_L
	$700	3 wks	81405
LAMP2 Gene Sequencing – lmLAMP2-a_L
	$700	3 wks	81405
LDB3 Gene Sequencing – lmLDB3-a_L
	$950	3 wks	81406
LMNA Gene Sequencing – lmLMNA-a_L
	$700	3 wks	81406
MYBPC3 Gene Sequencing – lmMYBPC3-a_L
	$1,500	3 wks	81407
MYH7 Gene Sequencing – lmMYH7-a_L
	$1,700	3 wks	81407
MYL2 Gene Sequencing – lmMYL2-a_L
	$700	3 wks	81405
MYL3 Gene Sequencing – lmMYL3-a_L
	$700	3 wks	81405
PKP2 Gene Sequencing – lmPKP2-a_L
	$1,500	3 wks	81479
PLN Gene Sequencing – lmPLN-a_L
	$400	3 wks	81479
PRKAG2 Gene Sequencing – lmPRKAG2-a_L
	$1,000	3 wks	81406
SCN5A Gene Sequencing – lmSCN5A-a_L
	$1,700	5-6 wks	81407
SGCD Gene Sequencing – lmSGCD-a_L
	$1,100	3 wks	81405
TAZ Gene Sequencing – lmTAZ-a_L
	$700	3 wks	81406
TCAP Gene Sequencing – lmTCAP-a_L
	$700	3 wks	81479
TMEM43 Gene Sequencing – lmTMEM43-a_L
	$700	3 wks	81479
TNNI3 Gene Sequencing – lmTNNI3-a_L
	$700	3 wks	81405
TNNT2 Gene Sequencing – lmTNNT2-a_L
	$1,000	3 wks	81406
TPM1 Gene Sequencing – lmTPM1-a_L
	$700	3 wks	81405
TTN Gene Sequencing – lmTTN-a_L
	$3,000	8-12 wks	81479
TTR Gene Sequencing – lmTTR-a_L
	$485	3 wks	81404
VCL Gene Sequencing – lmVCL-a_L
	$1,500	3 wks	81479

Congenital Heart Disease/Defects

	Price	TAT	CPT Codes
Congenital Heart Disease Panel A (GATA4, NKX2-5, JAG1) – lmCHD-pnlA_L
	$1,300	4 wks	81479
ELN (Elastin) Gene Sequencing – lmELN-a_L
	$1,300	4 wks	81479
GATA4 Gene Sequencing – lmGATA4-a_L
	$750	3 wks	81479
JAG1 Gene Sequencing – lmJAG1-a_L
	$1,100	3 wks	81407
NKX2-5 Gene Sequencing – lmNKX2-5-a_L
	$600	3 wks	81479

SOURCE:

http://pcpgm.partners.org/lmm/ordering/prices-CPTcodes_revised#Cardio_Header

Lakdawala NK, Funke BH, Baxter S, Cirino A, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M, Chung WK, Jones C, Psychogios A, Duffy E, Rehm HL, White E, Seidman JG, Seidman CE, Ho CY. Genetic Testing for Dilated Cardiomyopathy in Clinical Practice. J Card Fail 2012, In press.

Neri PM, Pollard SE, Volk LA, Newmark L, Varugheese M, Baxter S, Aronson SJ, Rehm HL, Bates DW. Usability of a Novel Clinician Interface for Genetic Results. J Biomed Informatics. 2012. In press.

Genomics @Brigham and Women’s Hospital and Harvard Medical School

The goal of The Cardiovascular Genome Unit (TCGU) is to foster interdisciplinary interaction between clinical investigators and scientists to comprehensively explore the era of human genomic research. In particular, our aim would be to identify, categorize and characterize the genes and genetic pathways of the vascular and cardiac tissues of the cardiovascular system during oncogenesis, normal function and the pathogenesis of cardiovascular diseases.

The Cardiovascular Genome Unit is responsible for indexing gene expression, profiling gene expression, identifying SNPs and generation of protein profiles from a wide variety of tissues representative of various anatomical regions as well as developmental and pathological stages in the cardiovascular system. This information resource emphasizes on cardiovascular disease and should aid in the discovery of disease causing genes, diagnostic and prognostic markers, drug targets, protein therapeutics and improved therapeutic strategies for cardiovascular disease.

Our laboratory is the curator of a genome-based resource for molecular cardiovascular medicine consisting of over 52,000 ESTs generated from nine heart and artery libraries, representing different developmental stages and disease states (Liew et al 1994, Hwang et al 1997, Dempsey et al 2000).

This comprehensive catalogue of cardiac and hematopoietic genes is an unmined molecular resource for microarray analysis and a genetic gold mine for the discovery of genes that may play a role in cardiovascular disorders. In order to exploit this raw data, we propose to develop cDNA microarrays consisting of known and novel sequence-tagged genes. The arrayed clones provide an excellent substrate for expression profiling of cardiovascular disease, for example heart failure or ischemic heart disease, leading the potential discovery of diagnostic as well as prognostic markers.

In order to accomplish the goals of the center, several cutting edge technologies are being employed.

The human cardiovascular research component of our labs.

One of the most efficient and effective strategies for the identification genes is the Expressed Sequence Tag (EST) approach. In this approach, randomly selected cDNA clones are subjected to automated sequencing (PCR or plasmid templates) to generate a partial sequence from either the 5’- or 3’-end termed an EST. This method allows for large-scale gene tagging and indexing from any tissue- or cell-type of interest. A comprehensive cardiovascular gene index could be developed using a variety of cardiovascular tissues representing different anatomical, developmental and pathological states.

Comparing transcript profiles between different development or disease states is a powerful way to gain insight into the genetic changes underlying these events. This is especially important when looking at complex systems, such as in development or disease (e.g. hypertension or atherosclerosis). There are several unique approaches to this problem, several of which are:

a) EST profile Comparison– After the production of a significant number of ESTs from 2 or more libraries, the frequencies of ESTs can be compared to identify those genes which are differentially expressed. However, normalized or subtracted cDNA libraries cannot be used for this and this method is most effective for finding large differences in expression.

b) cDNA Microarray Hybridization– The recent introduction of the cDNA microarray, a technology capable of analyzing the expression of thousands of genes simultaneously in a single experiment, may provide one of the best ways to delineate gene expression patterns. In the cDNA microarray, cDNA clones are spotted onto a glass slide matrix and hybridized with fluorescently labeled cDNA probes derived from total RNA pools of test and reference cells or tissues. The signal intensity for each probe is quantified and any differences between the two samples becomes readily apparent. Thus, the genetic changes underlying the phenotype of study can be identified at the level of a single gene.

c) Identification of Single Nucleotide Polymorphisms– SNPs are single-base heritable variations in the genome which occur once in approximately 1000 bases in the human genome and occur at a frequency of >1% in the human population. SNPs provide an important genetic resource useful for disease gene discovery. including the identification of disease susceptible genes. SNPs can be identified through comparison of EST sequences, DNA hybridization strategies and direct sequencing of genomic DNA. The generation of a SNP database for genes expressed in the cardiovascular system will provide a valuable resource to aid in disease gene discovery.

d) Quantitative determination of expressed genes– the up- and down- regulated genes are crucial to the phenotypic expression of any given cell. The frequency of gene expressed in development or disease state can be obtained from an EST approach using cDNA libraries as well as its intensity detected using microarrays. Such results can be verified through RT-PCR analysis from the tissue samples. A high through-put analysis of 96 samples can be performed by real-time PCR analyses.

Using our 10,000 element “CardioChip”, we elucidated over 100 differentially expressed genes in end-stage heart failure resulting from dilated cardiomyopathy. The results were published in

Am J Pathol. 2002 June; 160(6): 2035–2043.

Global Gene Expression Profiling of End-Stage Dilated Cardiomyopathy Using a Human Cardiovascular-Based cDNA Microarray

J. David Barrans,^*† Paul D. Allen,^‡ Dimitrios Stamatiou,^* Victor J. Dzau,^* and Choong-Chin Liew^*†

From Cardiovascular Genome Unit^*, the Department of Medicine, and the Department of Anesthesiology,^‡Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and the Department of Laboratory Medicine and Pathobiology,^†University of Toronto, Toronto, Ontario, Canada

Abstract

To obtain a genomic portrait of heart failure derived from end-stage dilated cardiomyopathy (DCM), we explored expression analysis using the CardioChip, a nonredundant 10,848-element human cardiovascular-based expressed sequence tag glass slide cDNA microarray constructed in-house. RNA was extracted from the left ventricular free wall of seven patients undergoing transplantation, and five nonfailing heart samples. Cy3- and Cy5-labeled (and reverse dye-labeled) cDNA probes were synthesized from individual diseased or nonfailing adult heart RNA, and hybridized to the array. More than 100 transcripts were consistently differentially expressed in DCM >1.5-fold (versus pooled nonfailing heart,P < 0.05). Atrial natriuretic peptide was found to be up-regulated in DCM (19-fold compared to nonfailing, P < 0.05), as well as numerous sarcomeric and cytoskeletal proteins (eg, cardiac troponin, tropomyosin), stress response proteins (eg, HSP 40, HSP 70), and transcription/translation regulators (eg, CCAAT box binding factor, eIF-1AY). Down-regulation was most prominently observed with cell-signaling channels and mediators, particularly those involved in Ca²⁺ pathways (Ca²⁺/calmodulin-dependent kinase, inositol 1,4,5-trisphosphate receptor, SERCA). Most intriguing was the co-expression of several novel, cardiac-enriched expressed sequence tags. Quantitative real-time reverse transcriptase-polymerase chain reaction of a selection of these clones verified expression. Our study provides a preliminary molecular profile of DCM using the largest human heart-specific cDNA microarray to date.

Dilated cardiomyopathy (DCM) is characterized clinically by left ventricular dilatation, wall thinning, and homogeneous dysfunction of the myocardium leading to congestive heart failure. Genetically, DCM seems to evolve through primary mutations in the genes of the sarcomeric proteins.¹ However, recent evidence suggests that, despite distinct pathways leading to divergent endpoint phenotypes of each disease, there may exist some overlapping genetic modifiers leading to a conversion of one to the other.² How this occurs is under question; to understand this, a better knowledge of the molecular pathways and intermediary regulators is required.

Global analysis of gene expression has proven to be a fruitful means of examining the overall molecular portrait of a particular event as well as seeking out novel candidate transcripts that may play a role in formulating the phenotype or genotype of interest. By using this strategy, multiple genes and pathways in complex disorders can be visualized simultaneously, allowing for a feasible platform from which to investigate new and interesting genes. Using expressed sequence tag technology, our laboratory has generated a compendium of genes expressed in the human cardiovascular system, with the ultimate goal of assembling the intricacies of development and of disease, particularly the pathways leading to heart failure.³ Through a computer-based in silico strategy, we have been able to identify—in a large scale—both known and previously unsuspected genetic modulators contributing to the growth of the myocardium from fetal through adult, and from normal to a perturbed hypertrophic phenotype. In contrast a gene-by-gene approach in elucidating the genes and mechanisms involved is time-consuming and cumbersome.

Recently, microarray technology has been used as a means of large-scale screening of vast numbers of genes—if not whole genomes—that possess differential expression in two distinct conditions. Although new and exciting developments have arisen in such fields as cancer⁴ and yeast,⁵ advances in understanding the complexity of cardiovascular disease,⁶ specifically DCM, have been limited. One recent study examined gene expression in two failing hearts using oligo-based arrays.⁷ Although the GeneChip^® (Affymetrix, Santa Clara, CA) offers a carefully controlled systematic method of analysis, its current lack of user flexibility in its design hinders novel gene discovery currently available in tissue-specific arrays. Our laboratory has taken advantage of our vast previously acquired resources and has constructed what we believe to be the first ever custom-made cardiovascular-based cDNA microarray, which we term the “CardioChip.”⁸ Its practicality and flexibility has allowed us to conceptualize the molecular events surrounding end-stage heart failure.

This report describes the most informative cDNA microarray-based analysis of end-stage heart failure derived from DCM currently available. Although we believe we have effectively demonstrated reproducibility and reliability of our technology (both for the entire array and for a selection of genes located on it), a larger n from our population would enhance the validity of our conclusions. Certainly, there exists no homogeneous heart failure genotype, especially among only seven DCM patients. Nonetheless, we have demonstrated a common expression pattern among our set of samples, from both microarray and QRT-PCR analysis. We are also limited by the genes (both in number and identity) present on this array. Although we are currently unable to spot every gene and gene cluster on our CardioChip, we have tried to draw from a diverse assortment of genes and gene pathways, both known and unknown. It must be emphasized that this investigation is not exhaustive; by no means does it attempt to fully characterize the molecular basis of heart failure. Its intention is to provide a preliminary portrait of global gene expression in complex cardiovascular disease using cDNA microarray and QRT-PCR technology, and to highlight the effectiveness of our ever-evolving platform for gene discovery. With even more patient samples and a CardioChip toward completeness, we will be in a better position to reap the important benefits from this initial work and expand our body of knowledge.

Am J Pathol. 2002 June; 160(6): 2035–2043.

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Liew CC, Takihara KY, Jandreski M, Liew J, Sole MJ. Structure and expression of human b-myosin heavy chain gene. In: Carraro U, editor. Sarcomeric and Non-sarcomeric Muscles: Basic and Applied Research Prospects for the 90s. Padova, Italy: Unipress
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Wang RX, Cukerman E, Chen B, Liew CC. Differential screening and megasequencing of human heart cDNA library: A search for genes associated with heart failure. In: Dhalla NS, Pierce GN, Panagia V, Beamish RE, editors. Boston: Kluwer Academic Press; 1995. P. 67-77.

Dempsey A, Liew CC. Genes involved in normal cardiac development. In: Sheridan DJ, editor. Left Ventricular Hypertrophy. London: Churchill Communications Europe Ltd; 1998: p. 61-70.

Tan K, Dempsey A, Liew CC. Cardiac genes and gene databases for cardiovascular disease genetics. In: Hollenberg NK, editor. Current Hypertension Reports. Philadelphia: Current Science Group; 1999: Vol 1:51-58.

Liew, CC. Expressed Sequence Tags. In: Encyclopedia of Molecular Medicine, Ed: T. Creighton, John Wiley and Son, New York. 2001

Hwang J-J, Dzau V and Liew CC. Genomics and thePathophysiology of Heart Failure. In: Current Cardiology Reports; Current Science Inc; 2001: Vol 3: 198-207.

http://issuu.com/pcpgm_lmm/docs/cmbig_lmmcardio/16

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Genetics of Intersexuality (Ambiguous Genitalia): Management of Patients

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged androgen, Androgen insensitivity syndrome, congenital, Congenital Adrenal Hyperplasia, genetic, gonad, Intersex, intersexuality, Klinefelter's syndrome, Sex assignment, syndrome, XY, XY sex-determination system on February 25, 2013| Leave a Comment »

Intersexuality: Management of Patients

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Introduction

Humans can be immensely strong and adaptable. Certainly some intersexed individuals can, in dignity, maintain themselves in a manner that they neither would have chosen nor in which they feel comfortable — as have others with a life condition from birth that cannot be changed (from cleft palate to meningomyelocele).

Many can adjust to surgery and reassignment for which they were not consulted and many have learned to accept secrecy, misrepresentations, white and black lies and loneliness. People make life accommodations every day and try to better their lot for tomorrow. Many individuals that have come to terms with their life regardless of how stressed or painful.

However, there are individuals who have been given neonatal surgery for cleft palate or meningomyelocele, many of those who have had genital surgery or been sex reassigned neonatally have complained bitterly of the treatment. Some have sex reassigned themselves. Others treated similarly have reasons not to make an issue of the matter but are living in silent despair but coping.

Guidelines

In all cases of ambiguous genitalia, to establish most probable cause, do a complete history and physical. The physical must include careful evaluation of the gonads and the internal as well as external genital structures. Genetic and endocrine evaluations are usually needed and interpretation can require the assistance of a pediatric endocrinologist, radiologist and urologist. Pelvic ultrasonography and genitography may be required. Do not hesitate to seek expert help; a team effort is best. The history must include assessment of the immediate and extended family.Be rapid in this decision making but take as much time as needed. Hospitals should have established House Staff Operating Procedures to be followed in such cases. Many consider this a medical emergency (and in cases of electrolyte imbalance this may be immediately so) nevertheless, it is believed that most doubt should be resolved before a final determination is made. It is simultaneously advised that all births be accompanied by a full genital inspection. Many cases of intersex go undetected.

Immediately, and simultaneously with the above, advise parents of the reasons for the delay. Full and honest disclosure is best and counseling must start directly. Insure that the parents understand this condition is a natural variety of intersex that is uncommon or rare but not unheard of. Convey strongly to the parents that they are not at fault for the development and the child can have a full, productive and happy life. Repeat this counseling at the next opportunity and as often as needed.

The child’s condition is nothing to be ashamed of but it is also nothing to be broadcast as a hospital curiosity. The child and family confidentiality must be respected.

In the most common cases, those of hypospadias and congenital adrenal hyperplasia (C.A.H.) diagnosis should be rapid and clear. In other situations, with a known diagnosis, declare sex based on the most likely outcome for the child involved. Encourage the parents to accept this as best; their desire as to sex of assignment is secondary. The child remains the patient. When assignment is based on the most likely outcome, most children will adapt and accept their gender assignment and it will coincide with their sexual identity.

The sex of assignment, when based on the nature of the diagnosis rather than only considering the size or functionality of the phallus, respects the idea that the nervous system involved in adult sexuality has been influenced by genetic and endocrine events that will most likely become manifest with or after puberty. In the majority of cases this sex of assignment will indeed be in concert with the appearance of the genitalia. In certain childhood situations, however, such assignment will be counter to the genital appearance (e.g., for reductase deficiency). The concern is primarily how the individual will develop and prefer to live post puberty when he or she becomes most sexually active.

Rear as male:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 1-3)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with extensively fused labia and a penile clitoris

XY individuals with Hypospadias

Persons with Klinefelter syndrome

XY individuals with Micropenis

XY individuals with 5-alpha or 17-beta reductase deficiency

Rear as female:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 4-7)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with hypertrophied clitoris

XX individuals with Gonadal dysgenesis

XY individuals with Gonadal dysgenesis

Persons with Turner’s syndrome

For those individuals with mixed gonadal dysgenesis (MGD) assign male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. The genital appearance of individuals with MGD can range from that of a typical Turner’s syndrome to that of a typical male. Evaluation of high male-like testosterone levels in these cases is also rationale for male assignment.

True hermaphrodites should be assigned male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. If there is a micropenis, assign as male. Admittedly, in some cases a clear diagnosis is not possible, the genital appearance will seem equally male as female and prediction as to future development and gender preference is difficult. There is little evidence a poorly functioning clitoris and vagina is any better than a poorly functioning penis and there is no higher reason to save the reproductive capacity of ovaries over testes. In such difficult cases, whichever decision is made, the likelihood of the individual independently switching gender remains. The medical team in such cases will be taxed to make the best management decision.

While sex determination is ongoing, the hospital administration can wait for a final diagnosis before entering a sex of record and Staff can refer to the child as “Infant Jones” or “Baby Brown.” After a sex designation has been made, naming and registration can occur. In those cases mentioned above, where prediction of future outcome is in doubt, parents might consider that a name be used that is appropriate for either males or females (e.g., Lee, Terry, Kim, Francis, Lynn, etc.).

Perform no major surgery for cosmetic reasons alone; only for conditions related to physical/medical health. This will entail a great deal of explanation needed for the parents who will want their children to “look normal.” Explain to them that appearances during childhood, while not typical of other children, may be of less importance than functionality and post pubertal erotic sensitivity of the genitalia. Surgery can potentially impair sexual/erotic function. Therefore such surgery, which includes all clitoral surgery and any sex reassignment, should typically wait until puberty or after when the patient is able to give truly informed consent.

Major prolonged steroid hormone administration (other than for management of C.A.H.) too should require informed consent. Many intersex or sex reassigned individual’s have felt they were not consulted about their use and effects and regretted the results.

In individuals with A.I.S, do not remove gonads for fear of potential tumor growth; such tumors have not been reported to occur in prepubertal children. Retention of the gonads will forestall the need for hormone replacement therapy and possibly help reduce osteoporosis.Furthermore, delaying gonadectomy until after puberty will allow the young woman to come to terms with her diagnosis, understand the reason for her surgery and participate in the decision.
Advice regarding gonad removal from true hermaphrodites, individuals with streak gonads and others where malignancies can potentially occur is not so clear. Prophylactically it is common to remove these early; particularly in cases of gonadal dysgenesis.Watchful waiting with frequent checks is always prudent. It is suggested, whenever the gonads are removed, is to explain as best as possible why the procedure is needed and attempt to get consent. If the child is too young to understand the reason for the surgery, its necessity should be explained as early as possible.

In rearing, parents must be consistent in seeing their child as either a boy or girl; not neuter. In the society intersex is a designation of medical fact but not yet a commonly accepted social designation. With age and experience, however, an increasing number of hermaphroditic and pseudohermaphroditic individuals are adopting this identification. In any case, advise parents to allow their child free expression as to choices in toy selection, game preference, friend association, future aspirations and so forth.

Offer advice and tips on how to meet anticipated situations, e.g., how to deal with grandparents, siblings, baby sitters and others that might question the child’s genital appearance (e.g., “He/she is different but normal. When the child is older he/she and the doctors will do what seems best.”) Parents should minimize the opportunities for such questioning by strangers.

Be clear that the child is special and, in some cases might, before or after puberty, accept life as a tomboy or a sissy or even switch gender altogether. The individual may demonstrate androphilic, gynecophilic or ambiphilic orientation. These behaviors are not due to poor parental supervision but will be related to an interaction of the biological, psychological, social and cultural forces to which a child with intersexuality is subject. Some individuals will be quite sexually active and others will be altogether reserved and have little or no interest in sexual relationships.

The patient’s special situation will require guidance as to how to meet potential challenges from parents, peers and strangers. He or she will need love and friendly support.Not all parents will be helpful, understanding, or benign and childhood, adolescent, and adult peers can be cruel. Positive peer interaction should be facilitated and encouraged.

Maintain contact with family so that counsel is available particularly at crucial times.Counseling should be multi-staged (at birth, and at least again at age two, at school entry, prior to and during pubertal changes, and yearly during adolescence) and it should be detailed and honest. Counseling should be straight-forward, neither patronizing or paternalistic, to parents and to the child as he or she develops with as much full disclosure as the parents and child can absorb. The counseling should ideally be by those trained in sexual/gender/intersex matters.

As the child matures there must be opportunity for private counseling sessions and it is essential the door remains open for additional consultation as needed. On the one hand, the full impact of the situation will not always be immediately apparent to the parents or child. On the other hand, they might magnify the developmental potential of the genital ambiguity. As above, the counseling should ideally be by those trained in sexual/gender/intersex matters.

Counseling must include developmental sequelae to be anticipated. This should be along medical/biological lines and along social/psychological lines. Do not avoid honest and frank talk of sexual and erotic matters. Discuss the probabilities of puberty such as the presence or absence of menses and the potential for fertility or infertility. Contraception advice may be needed and safe-sex advice is always warranted. Certainly the full gamut of heterosexual, homosexual, bisexual and even celibate options –however these are interpreted by the patient– must be offered and candidly discussed. Adoption possibilities can be broached for those that will be infertile. It is better to discuss these issues early rather than late. Do not obfuscate; knowledge is power enabling the individuals to structure their lives accordingly.

The family should be encouraged to openly discuss the situation among themselves, with and without a counselor present, so the child and parents can honestly come to terms with whatever the future holds. Parents have to understand their child’s needs and feelings and the child has to understand the concerns of the parents.

As early as possible put the family in touch with a support group. There are such groups for individuals with Androgen Insensitivity Syndrome, Congenital Adrenal Hyperplasia, Klinefelter Syndrome, and Turner’s Syndrome. Intersexed individuals as a whole (hermaphrodites and pseudohermaphrodites of all etiologies) have a support group, the Intersex Society of North America [addresses for these groups are listed below]. It is emphasized that one on one contact with another person having similar experiences can be the most uplifting factor in an intersexed person’s healthy development! Individual groups or chapters might be more inclined toward parental concerns while others might be tilted toward the intersexed person’s concerns. Both perspectives are needed and separate meetings for each faction are useful. Parents need to talk about their feelings in an environment free of intersexed children and adults and the intersexed children and adults similarly need to be able to discuss their feelings and concerns free of their parents. There are times when it is appropriate for physicians to be present and times when it is not.

Keep genital inspection to a minimum and request permission for inspection even from a child. Hold in mind that a child may not feel able to deny a physician’s request even though that might be his/her wish. The individuals must come to realize that their genitals are their own and they, not the doctors, parents or anyone else, have control over them. Allow others to view the patient only with his or her permission. Often the genital inspections themselves become traumatic events.

Let the child grow and develop as normally as possible with a minimum of interference other than needed for medical care and counseling. Let him/her know that help is available if needed. Listen to the patient; even when as a child. The physician should be seen as a friend.

With increasing maturity the designation of intersex may be acceptable to some and not to others. It should be offered as an optional identity along with male and female.

As puberty approaches be open and honest with the endocrine and surgical options and life choices available. Be candid at the sexual/erotic and other trade-offs involved with surgery or gender change and insure that any decision finally be that of the fully informed individual regardless of age. To have him/her discuss the treatment with someone who has undergone the procedure is ideal.

Most individuals are convinced by the age of 10-15 as to the direction that would be most suitable for them; male or female. Some decisions, however, should be stalled as long as possible to increase the likelihood that the individual has some experience with which to judge. For instance, a female with a phallic clitoris, sexually inexperienced with partner or masturbation, may not realize the loss in genital sensitivity and responsivity that can accompany cosmetic clitoral reduction. Insure that sufficient information is provided to aid in any decision.

Most intersex conditions can remain without any surgery at all. A woman with a phallus can enjoy her hypertrophied clitoris and so can her partner. Women with the androgen insensitivity syndrome or virilizing congenital adrenal hyperplasia who have smaller than usual vaginas can be advised to use pressure dilation to fashion one to facilitate coitus; a woman with partial A.I.S. likewise can enjoy a large clitoris. A male with hypospadias might have to sit to urinate without mishap but can function sexually without surgery. An individual with a micropenis can satisfy a partner and father children.There is disagreement as to whether gonads that might prove masculinizing or feminizing at puberty should be removed early on to prevent such changes in a child that does not desire such changes. The disagreement involves the concept that the individual faced with such changes might actually come to prefer them to the habitus of rearing but will only become aware of them post hoc. The bias is to leave them in so any genetic-endocrine predisposition imposed prenatally can come to be activated with puberty. It is admitted that however there is no good body of clinical data from which the best prognosis can be made in such cases. There are some indications, however, that even without the gonads the adrenals might prod pubertal changes.

If a gender change is being considered, have the individual experience a real-life living test. In this way the individual will have first hand experience in how it actually is to live in the other role. Experience has shown that most indeed make the switch permanent but some return to their original sex of rearing. Some, usually as adults, will accept an identity as an intersex and plot their own course.

Maintain accurate medical, surgical, and psychotherapy records of all aspects of each case. This will facilitate whatever treatment is needed and assist in future research to enhance management of subsequent intersex cases. These records should be available to the patient.

Whenever possible, long term follow-up evaluations, e.g., at 5, 10, 15, and even 20 years of age, should become part of the record.

Last, it is believed that information and advice may be provided as much as possible but not to be “authoritarian” in the actions. The postpubertal individual must be allowed time to consider, reflect, discuss and evaluate and then, have the last word in his or her genital modification and gender role and final sex assignment.

CASE STUDY

European Congress of Endocrinology 2008

Berlin, Germany
03 May 2008 – 07 May 2008
European Society of Endocrinology

Endocrine Abstracts (2008) 16 P589

Hypospadias and micropenis in congenital adrenal hyperplasia: a case study

Sandra Fleischer, Ute S Groß, Hjördis HS Drexler, Achim Wüsthof & Heinrich M Schulte

Endokrinologikum Hamburg, Hamburg, Germany.

Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases with increased adrenal androgens secretion from the adrenal cortex, characterized by simple virilizing and salt wasting forms. Deficiency of 21-hydroxylase, caused by mutations in the 21-hydroxylase gene (CYP21A2) is the most frequent CAH, accounting for more than 90 percent of CAH cases. Deficiency of 3 beta-Hydroxysteroid-Dehydrogenase Type II is caused by mutations in the HSD3B2 gene and accounts for about 1–10 percent of cases of CAH.

Patient: This report is about a 2-year-old patient of Turkish origin referred to our center with clinical finding of penoscrotal hypospadias and micropenis (stretched penile length 1.5 cm). Testicles were palpable bilaterally in the scrotum. Due to initial biochemical and hormonal findings moleculargentic analysis of CYP21A2 gene was already done, showing heterozygous germline mutations p.Val281Leu, p.Leu307fs, p.Gln318Stop and p.Arg356Trp. His parents are cousin-german to each other.

Methods: Genomic DNA was extracted from peripheral blood leukocytes. Coding regions and corresponding exon-intron boundaries of the CYP21A2 gene and the HSD3B2 gene were amplified by PCR and subjected to direct sequencing.

Results: A compound heterozygous state of these mutations was excluded by sequencing analysis ofCYP21A2 genes of both parents (father has no mutation). Further hormonal studies suggested a 3 β-Hydroxysteroid dehydrogenase type II deficiency and justified sequence analysis of the HSD3B2 gene. A novel homozygous germline mutation (p.Trp355Arg) was found, for which both parents are heterozygous carriers.

Conclusion: To judge a case of CAH in the right way it is important to look at all clinical aspects in a differentiated way. Comprehensive (clinical, biochemical, hormonal) analysis should be conducted and approved by moleculargenetic analysis in line with a genetic counseling.

REFERENCES

http://www.ukia.co.uk/diamond/diaguide.htm

http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1997-management-of-intersexuality.html

Endocrine Abstracts (2008) 16 P589

References on Ethics and Treatment Options:

^ David A. Warrell (2005). Oxford textbook of medicine: Sections 18-33. Oxford University Press. pp. 261–. ISBN 978-0-19-856978-7. Retrieved 14 June 2010.
^ Aubrey Milunsky; Jeff Milunsky (29 January 2010). Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. John Wiley and Sons. pp. 600–. ISBN 978-1-4051-9087-9. Retrieved 14 June 2010.
^ Richard D. McAnulty, M. Michele Burnette (2006) Sex and sexuality, Volume 1, Greenwood Publishing Group, p.165
^ Elton, Catherine (2010-06-18). “A Prenatal Treatment Raises Questions of Medical Ethics”. TIME. Retrieved 2010-07-05.
^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (2010-06-29). “Preventing Homosexuality (and Uppity Women) in the Womb?”. Bioethics Forum, a service of the Hastings Center. Retrieved 2010-07-05.
^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (30 July 2012). “Prenatal Dexamethasone for Congenital Adrenal Hyperplasia”. Journal of Bioethical Inquiry. Retrieved 3 August 2012.
^ Fernández-Balsells, M.M.; K. Muthusamy, G. Smushkin, et al (2010). “Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: A systematic review and meta-analyses”. Clinical Endocrinology 73 (4): 436–444. Retrieved 3 August 2012.
^ Bongiovanni, Alfred M.; Root, Allen W. (1963). “The Adrenogenital Syndrome”. New England Journal of Medicine 268 (23): 1283.doi:10.1056/NEJM196306062682308.

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Mobilizing Scientific Societies: Editorial by Science Editor-in-Chief Dr. Bruce Alberts

Posted in Health Economics and Outcomes Research, HealthCare IT, Interviews with Scientific Leaders, Scientist: Career considerations, tagged AAAS, Aviva Lev-Ari, Bruce Alberts, Chronicle of Higher Education, Educational Resources, health, medicine, National Science Foundation, science, Science education, STEM, United States on February 24, 2013| Leave a Comment »

Mobilizing Scientific Societies: Editorial by Science Editor-in-Chief Dr. Bruce Alberts

Reporter: Stephen J. Williams, Ph.D

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WordCloud Image Produced by Adam Tubman

In a weekly editorial, Dr. Bruce Alberts, Editor-in –Chief of the journal Science discussed issues pertaining to science education in the United States[1]. He suggests the US science education system may need to be more flexible in its approach to science education in grade and high school. He considers the one major problem is the “broad coverage of each subject, which kills student interest and makes genuine comprehension impossible. Dr. Alberts suggest that state-based textbooks and the inability of the scientific community to understand teacher’s needs is driving this inadvertent problem. The current textbooks used for scientific education focus more on memorization of a multitude of scientific terms than on concept development, experimentation and inquisition, and conclusion. Materials are desperately needed for teachers to guide students to confront the overall concept, and working in teams, design potential methods to further explore these concepts. He suggest this style of teaching would require close partnerships between top-notch teachers , educational experts and scientific societies in order to research the effect of current curriculum materials but also develop new Web-based curriculum.

In a recent interview in the March 2013 issue of Wired magazine with Clayton Christensen, Ph.D. the author of the famed book The innovator’s Dilemma, Dr. Christensen forwqarns the impending changes in higher education due to increased availability of online learning. As he states, universities are on the precipice of a collapse in the future and those which survive will evolve hybrid models of education, part online and part classroom but will provide more specialized offerings to fit current needs. Indeed, as listed below these changes and suggestions in science education may well be underway. Below is a brief listing of scientific societies who have undertaken these challenges and formed extensive programs in STEM education.

FASEB (Federation of American Societies for Experimental Biology) programs such as:

Resources for Faculty and K-12 Teachers

APS Frontiers in Physiology Program – Provides professional development for middle and high school teachers by providing them with tools and resources and connecting them with researchers on-line and through workshops.

APS Physiology Understanding Week – Fosters relationships among teachers, students, and physiologists. PhUn Week encourages member physiologists across the nation to volunteer and work with teachers in their local community to visit a classroom during the first week in November.

Leap to the Top in Science Classes from AAAS found at:

http://news.aaas.org/2013_annual_meeting/0214leap-to-the-top-in-science-classes.shtml

A progress report from the 2013 AAAS meeting follows:

Often, in the daily grind of slogging through a difficult science class, students see fully formed scientists and their discoveries as a distant blur. Remote men and women somehow make advanced science happen.

New efforts aim to bring students face to face with creative, imaginative scientists right in their classroom.

With a lifetime of scientific contributions at their back, many retired scientists, engineers, and physicians are returning to school, not as pupils or as instructors, but as classroom volunteers in public elementary, middle, and high schools.

This week over 400 teachers and scientists gathered in Boston for the first International Teacher-Scientist Partnership Conference, organized by AAAS Education and Human Resources and the University of California, San Francisco Science & Health Education Partnership, sponsored by the National Science Foundation. Presenters are scheduled to share a range of partnership models over three days, from scientists generating digital education tools, to teachers participating in research.

Throughout the first day of the conference, the conversation turned to the idea of bringing scientists into the classroom to work directly with the students.

Virginia Shepherd from Vanderbilt University shared a comprehensive analysis of the university’s nearly 20-year-old Graduate STEM Fellows in K-12 Education program. Presentation attendees duly applauded the success of the program but said that they had trouble establishing similar programs in their state for lack of funding.

A handful of organizations represented at the conference have found that an affordable way to bring scientists into the classroom is to recruit retired scientists.

Volunteers at Northeastern University’s Retirees Enhancing Science Education through Experiments and Demonstrations program, or RE-SEED, spend at least one day a week in an elementary, middle, or high school classroom in Massachusetts helping students conduct experiments as part of the existing curriculum.

“Retired scientists and engineers have a lot of experience from a lifetime of working in laboratories. They can make what the students are learning relevant,” said Christos Zahopoulos, a professor of education and engineering at Northeastern University.

Since founding RE-SEED in 1991, Zahopoulos has helped to start similar programs in 15 states, conducting on-site trainings for volunteers. While such programs start out strong, many of them have since faded, with only a handful remaining, he said.

Even though retirees are offering a free service to the schools, getting them trained and placed takes a certain amount of funding, Zahopoulos says. He has been fortunate to fund RE-SEED with private donations. Many programs were not so lucky.

AAAS’ Senior Scientists and Engineers (SSE), a service-oriented organization for retired scientists and engineers, has managed to sustain a similar program for seven years. In 2005, Zahopoulos helped SSE establish its own volunteer program.

Donald Rea, a former research chemist for NASA’s Jet Propulsion Laboratory and SSE volunteer coordinator for Virginia, hopes that helping to reinforce science education will enhance the public understanding of science in years to come.

“If you want to have an influence on science literacy, you want to get [kids] while they are young. So we work in classrooms as young as second grade,” Rea said.

This kind of investment takes many years to fully mature. So, how do Rea and Zahopoulos measure success? They look to their teachers, volunteers, and students.

Rea said he measures success by the eagerness of schools and teachers to participate year after year.

For Zahopoulos, hints of success sometimes come in the mail. He says one student wrote in to RE-SEED upon graduating from high school, several years after any contact with a RE-SEED volunteer, to say that she had decided to major in biology and had enrolled in a pre-medicine program.

Both Rea and Zahopoulos said they have been amazed at the dedication and eagerness of volunteers.

“When we first started, we asked volunteers to commit to one day a week for one year. Now we have volunteers who have been with us for 18 years and some volunteer as many as 4 times per week,” Zahopoulos said.

Ron McKnight, a former Department of Energy physicists and SSE volunteer has recently taken on the task of coordinating volunteers living in Montgomery County, Md. He still volunteers in middle school science classrooms and is considering taking on another assignment.

When asked what he loves about volunteering, he replied, “Whenever a kid I’m working with asks a really good question, that’s when I have a really good day.”

National Science Foundation (NSF) Research on Learning in Formal and Informal Settings (DRL)

Information can be found at http://www.nsf.gov/div/index.jsp?div=DRL

DRL invests in projects to improve the effectiveness of STEM learning for people of all ages. Its mission includes promoting innovative research, development, and evaluation of learning and teaching across all STEM disciplines by advancing cutting-edge knowledge and practices in both formal and informal learning settings. DRL also promotes the broadening and deepening of capacity and impact in the educational sciences by encouraging the participation of scientists, engineers, and educators from the range of disciplines represented at NSF. Therefore, DRL’s role in the larger context of Federal support for education research and evaluation is to be a catalyst for change—advancing theory, method, measurement, development, and application in STEM education. The Division seeks to advance both early, promising innovations as well as larger-scale adoptions of proven educational innovations. In doing so, it challenges the field to create the ideas, resources, and human capacity to bring about the needed transformation of STEM education for the 21st century.

Society of Toxicology K-12 Educational Outreach for Scientists

http://www.toxicology.org/ai/k12o/k-12scientists.asp

This sites contains multiple .pdf files on volunteering and mentoring topics including

Scientist Mentor Ideas
Links to Other Mentoring Sites
Resources for toxicologists to use in K-12 Outreach
Regional Chapter K-12 Outreach

References:

1. Alberts B: Mobilizing scientific societies. Science 2012, 338(6113):1396.

for high school teachers please see https://www.teachercertificationdegrees.com/top-blogs/science-teacher/

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Archive for February, 2013

Heart Vasculature – Regeneration and Protection of Coronary Artery Endothelium and Smooth Muscle: A Concept-based Pharmacological Therapy of a Combination Three Drug Regimen including THYMOSIN

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Induced Pluripotent Stem Cells? (iPS Cells)

Multipotent Embryonic Isl1^+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification

Thymosin beta 4 (Tβ4)

Clinical Study Data of Thymosin beta 4 Presented

Theoretical treatment protocol differential between the Preoperative which may be between 3 to 6 month, and the Postoperative which may prolong to one year.

Thymosin beta4 Induces Adult Epicardial Progenitor Mobilization and Neovascularization

A Concept-based Pharmacologic Therapy of a Combined Three Drug Regimen for Regeneration and Protection of Coronary Artery Endothelium and Smooth Muscle.

Original Drug Therapy Combination Proposed

Phase III Clinical Trials

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At $3 Million, New Award Gives Medical Researchers a Dose of Celebrity

By DENNIS OVERBYE in the New York Times

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Scientists Receive a New Physics Prize

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Simon Dawson/Bloomberg News

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Genomics and Ethics: DNA Fragments are Products of Nature or Patentable Genes?

Experts say court’s decision on human gene patents is a win-win

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Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

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Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

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Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Goes to Clinic @MGH: Clinically validated versions of Exome Sequencing and Analysis using Broad-developed methods like Hybrid Capture, the Genome Analysis Toolkit (GATK), and MuTect

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DNA Sequencing

Services by Project Goals

Mutation Identification via Resequencing

Research Services

Technology Development

Clinical Diagnosis

Genomic Sequencing Projects

Advancing Translational Genomics through Personalized Medicine Projects

Harvard Medical School Genetics Training Program

Cardiovascular Research Center @MGH

Genomics and Cardiovascular Medicine @MGH

Translational Medicine: Genomics and Proteomics @MGH

Genetic Basis of Cardiomyopathy

Original gene identification for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant

Pan Cardiomyopathy Panel

Thymosins in Health and Disease II: 3^rd International Symposium on The Emerging Clinical Applications of Tymosin beta 4 in Cardiovascular Disease