Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
The Implications and Association of Stair Climbing with Atherosclerotic Cardiovascular Disease (ASCVD)
Reporter: Arav Gandhi, Research Assistant 2, Domain Content: Cardiovascular Diseases, Series A
Atherosclerotic Cardiovascular Disease (ASCVD) is a condition in which cholesterol builds up in the arteries to an extent that develops long-term complications for other areas of the body and in some cases emergence of symptoms such as chest pain, dizziness, and shortness of breath are presented and reported to PCPs. This can cause a strain on daily activities such as walking and especially may be noticed when climbing stairs which represents a form of exertion related to elevation. To further understand the significance of ASCVD upon daily activities, Zimin Song et al. (2023), using a sample of 458,860 participants (55.9% female) from the UK Biobank, aimed to evaluate the intensity of stair climbing and the present risk of ASCVD. All participants had a history of ASCVD, put at risk for ASCVD, or had a recorded levels of genetic risk.
Prior to the study, all participants underwent blood tests and other necessary measurements. During the study, the researchers assessed the intensity of stair climbing through a self-reported structure in which participants were asked a set of questions addressing the duration of climbing stairs and whether they continued to climb. Additional questionnaires were administered to collect sociodemographic characteristics, lifestyle factors, and health status. Following the conclusion of the study, the researchers found, with an application of statistical analysis, that over a period of 12.5 years individuals with a higher intensity of stair climbing were of younger age, female, and non-regular smokers. Moreover, those individuals exemplified a higher level of education and income along with healthier dietary habits and prolonged exercise durations. Beyond demographic characteristics, researchers found that when individuals especially those with a family history of ASCVD increased the intensity of stair climbing, the risk of ASCVD was reduced. This remained consistent across other groups of participants finding an association between the intensity of stair climbing and the risk of ASCVD.
Ultimately, given the large sample of UK adults, the findings conclude that high-intensity climbing, or climbing more than five flights of stairs daily was associated with over a 20% reduction in risk of obtaining ASCVD. Despite the variance of disease tendencies among individuals, active engagement in stair climbing can significantly reduce the risk of ASCVD in contrast to those who discontinued stair climbing leading to a higher risk of ASCVD. However, the intensity of stair climbing was limited to a threshold in which it no longer decreased the risk of ASCVD.
Simply climbing stairs can be considered a prevention strategy for ASCVD, but the application of active engagement in physical activities may be associated with reducing the risk of obtaining other diseases. For instance, the positive effects of stair climbing on reducing the risk of ASCVD may also apply to
atrial fibrillation,
diabetes, and
hypertension.
Other existing studies find associations with a
lower risk of metabolic syndrome, and even
mortality.
In contrast to structured sports and exercise, stair climbing proves to be an effective method with minimal equipment and low cost that allows an individual to practice cardiorespiratory fitness reducing the risks of various diseases while improving their overall standard of life. Although further studies need to be conducted on the extent to which intense stair climbing improves different areas of the body and what diseases it helps prevent, current studies prove the effects of stair climbing to be beneficial to an extent in which individuals should be encouraged in incorporate it in their daily routine yielding both short-term and long-term benefits.
To learn more about the topic, check out the article below.
SOURCE
Song Z, Wan L, Wang W, et al. Daily stair climbing, disease susceptibility, and risk of atherosclerotic cardiovascular disease: A prospective cohort study. Atherosclerosis. 2023:117300. doi: 10.1016/j.atherosclerosis.2023.117300
Other related articles published in this Open Access Online Scientific Journal include the following:
Archive for the ‘Atherogenic Processes & Pathology’ Category
The Current Impact and Future of Technology within Cardiovascular Surgery
Reporter: Arav Gandhi, Research Assistant 2, Domain Content: Cardiovascular Diseases, Series A
Medical professionals have been able to explore new methods and strategies to tackle complex medical conditions, especially with the limitations of other pre-existing conditions. For instance, through recent cardiology advancements, if the patient requires a heart transplant due to heart failure disease and is unable to undergo a human donor heart transplant as a result of pre-existing disease conditions or existing internal bleeding complications, there is a greater alternative to leaving it untreated. Medical professionals developed alternatives to humman donor transplants. One such a solution is transplanting a genetically modified pig heart, a new advanced experimental procedure that has been used over recent cases. Researchers continue to develop solutions that not only presents an alternative to current methods but also continue to maximize the potential of medical devices technology and of our understanding of medicine.
Recently, cardiologists at Henry Ford Health Hospital found themselves as the first physicians in the United States to employ an investigational device to treat a patient with severe tricuspid regurgitation. Having never been experimented upon prior to the situation, the K-Clip Transvascular Tricuspid Repair System utilizes a corkscrew anchor, which then clips the ring-shaped region of the valve. Similar to most dire situations where new technology is used, the patient, an 85-year-old male, continued to experience worsening symptoms for an entire year. His tricuspid valve, key in ensuring blood flow to the right ventricle and then to the pulmonary valve, was enlarged from his condition, resulting in the mass of his heart tripling in size. Cardiologists were then prompted to either utilize the new procedure or go untreated. With optimism, the cardiologists selected the procedure and applied a unique approach of an incision through the neck to reduce further risks of opening the chest and placed the device using real-time 3D imaging and 4D modeling. The medical professionals followed a minimally invasive procedure through the neck in contrast to traditional open-heart surgery and effectively employed recent advancements in imaging and modeling to ensure precision when planting the device, a new artificial tricuspid valve. The patient was later reported to have experience improve in the valve condition and a significant decrease in leakage, along with an improvement in his overall quality of life.
As a result, researchers should continue to focus not only on understanding undiscovered diseases and complications but also on developing alternative solutions to resolve cases in which the best practice approach can not be applied.
With the advancements in technology, the true extent of its application can not be discovered without experimentation and the application of imaging and other devices to resolve certain conditions. Beyond the technology itself, the introduction of new methods allows for less costly treatment plans, aiding especially those who come from a low-income background and currently struggle to afford basic healthcare. In the united States they are covered by MedicAid at all ages and by Medicare at age 65 and beyond. This is not the case in many countries in the World excluding Europe. The overall development of the field of medicine through advancement of medical technologies can indirectly allow for a improvement to the overall Global health care delivery and ascertain an increased life expectancies. This is primarily true, chiefly, in developing countries where established surgeries to resolve complex medical conditions still have the ability to achieve life-changing quality of life and longevity.
To learn more about the topic, check out the article below.
Chapter 13: Valve Replacement, Valve Implantation and Valve Repair
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
As catheter techniques evolved to compete with bypass surgery they progressed from balloon cracking of obstructive lesions (POBA=plain old balloon angioplasty) to placement of stents (wire fences). Surgeons sometimes use in-stent valves, and now devices analogous to in-stent valves can be placed by catheter for valve replacement in patients with too much co-morbidity to go through heart surgery. Aortic valve replacement by stent (TAVR) has had sufficient success to be considered for all patients who have sufficient impairment to merit intervention. The diameter is large, so a vascular surgeon participates in the arterial access and repair of the access site.
13.5 Tricuspid Valve
13.5.1 First-in-Man Mitral Valve Repairs Device used for Tricuspid Valve Repair: Cardioband used by University Hospital Zurich Heart Team
Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use
In this curation we wish to present two breaking through goals:
Goal 1:
Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer
Goal 2:
Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.
According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.
These eight subcellular pathologies can’t be measured at present time.
In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.
Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases
Glycation
Oxidative Stress
Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
Membrane instability
Inflammation in the gut [mucin layer and tight junctions]
Epigenetics/Methylation
Autophagy [AMPKbeta1 improvement in health span]
Diseases that are not Diseases: no drugs for them, only diet modification will help
Image source
Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease
These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:
Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL
In the Bioelecronics domain we are inspired by the work of the following three research sources:
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC
PENDING
THE VOICE of Stephen J. Williams, PhD
Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes
25% of US children have fatty liver
Type II diabetes can be manifested from fatty live with 151 million people worldwide affected moving up to 568 million in 7 years
A common myth is diabetes due to overweight condition driving the metabolic disease
There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
Thirty percent of ‘obese’ people just have high subcutaneous fat. the visceral fat is more problematic
there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects. Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
At any BMI some patients are insulin sensitive while some resistant
Visceral fat accumulation may be more due to chronic stress condition
Fructose can decrease liver mitochondrial function
A methionine and choline deficient diet can lead to rapid NASH development
W. Gerald “Jerry” Austen, MD influential in the design and creation of a cardiopulmonary (heart-lung) bypass machine and the intra-aortic balloon pump at MGH as renowned cardiac surgeon
Curator and reporter: Aviva Lev-Ari, PhD, RN
This article is classified in the ontology of LPBI Group’s Journal PharmaceuticalIntelligence.com under the Category of Research
Interviews with Scientific Leaders
This category includes 300 articles. LPBI Group’s will publish in July 2023 its Library of Audio Podcasts on “Interviews with Scientific Leaders.”
The presentations in the video below, about W. Gerald “Jerry” Austen, MD contributions to cardiac surgery are considered to be testimonials as well as qualify as “Interviews with a Scientific Leader” in the domains of cardiac surgery and cardiac repair medical devices with a special focus on:
cardiopulmonary (heart-lung) bypass machine, and
the intra-aortic balloon pump
On these two domains, LPBI Group had published extensively as the sources cited, below: Articles, e-Books in English and Spanish and Chapters in these book on the very specialty of Dr. Austen as included in the title of this article.
Recently, Mass General celebrated the life and legacy of W. Gerald “Jerry” Austen, MD — a renowned cardiac surgeon, beloved family man and visionary leader.
SOURCE
In Memoriam: W. Gerald Austen, MD – Mass General Giving
For 70 years, Dr. Austen was part of the Mass General community, having completed his residency at the hospital and continuing to become one of the most distinguished and well-regarded physicians in the hospital’s more than 200-year history. At 39 years old, he was named Mass General’s chief of surgical services — a position he held for nearly 29 years. Under his leadership, the Department of Surgery became one of the greatest academic departments of surgery in the country. Among his many contributions, he was influential in the design and creation of a cardiopulmonary (heart-lung) bypass machine and the intra-aortic balloon pump.
Hundreds of Dr. Austen’s closest friends, colleagues and family members gathered at Boston Symphony Hall to commemorate his legacy. A variety of speakers — from current Mass General President David F. M. Brown, MD, to former hospital President Peter Slavin, MD, and retired Chairman, President and CEO of Abiomed Mike Minogue — shared fond memories of Dr. Austen, further illustrating his unmatched and lasting impact on others.
The Mass General community will continue to mourn the loss of such a giant in the medical world and will carry on Dr. Austen’s legacy through compassionate care and an unparalleled commitment to all patients.
Susan Hockfield, ex-President of MIT delivered a speech about mechanical engineering and biomedicine, medical devices and cardiac repair devices. How proud Dr. Austen was about his MIT education and functions he fulfilled for this institutions and others.
Other related contributions on the specialty of Dr.W. Gerald “Jerry” Austen, MD – cardiac surgery are covered in e-books and articles on this Open Access Online Scientific Journal, include the following:
Articles
319 articles in the Cardiac and Cardiovascular Surgical Procedures Category
98 articles in the Aortic Valve Category
Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement
Chapter 13: Valve Replacement, Valve Implantation and Valve Repair
13.2 Aortic Valve
13.2.1 New method for performing Aortic Valve Replacement: Transmural catheter procedure developed at NIH, Minimally-invasive tissue-crossing – Transcaval access, abdominal aorta and the inferior vena cava
13.2.4 Surgical Aortic Valve Replacement (SAVR) vs Transcatheter Aortic Valve Implantation (TAVI): Results Comparison for Prosthesis-Patient Mismatch (PPM) – adjusted outcomes, including mortality, heart failure (HF) rehospitalization, stroke, and quality of life, at 1 year
13.2.6 Off-Label TAVR Procedures: 1 in 10 associated with higher in-hospital 30-day mortality, 1-year mortality was similar in the Off-Label and the On-Label groups
13.2.11 One year Post-Intervention Mortality Rate: TAVR and AVR – Aortic Valve Procedures 6.7% in AVR, 11.0% in AVR with CABG, 20.7 in Transvascular (TV-TAVR) and 28.0% in Transapical (TA-TAVR) Patients
13.2.16 The Centers for Medicare & Medicaid Services (CMS) covers transcatheter aortic valve replacement (TAVR) under Coverage with Evidence Development (CED)
Chapter 7: Ventricular Failure: Assist Devices, Surgical and Non-Surgical
7.1 Trends in the Industry
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
In addition to minimally invasive treatments for coronary disease and valve disease, there are minimally invasive alternatives to heart transplant for the dangerously weak heart (extreme heart failure) which can otherwise result in Cardiogenic Shock. These involve various means to augment or complement the pumping function of the heart, such as a Ventricular Assist Device (VAD) .
With respect to the performance of Mitral Valve Replacement, the current practice favors bioprosthetic valves over mechanical valve replacement for most patients, initially just used for elderly to avoid need for coumadin, but now used at younger ages due to improvements in longevity of the bioprosthetic valves, plus less damage to red cells.
7.1.2 Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia
7.2.4 Experimental Therapy (Left inter-atrial shunt implant device) for Heart Failure: Expert Opinion on a Preliminary Study on Heart Failure with preserved Ejection Fraction
7.3.1 Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Chapter 11: Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty
11.1 Hybrid Cath Lab/OR Suite
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
In an uncommon reversal of opinion, the combined forces of the American Heart Association (AHA) and the American College of Cardiology (ACC) reviewed compelling data and reversed a prior assessment on the need for an on-site cardiovascular surgery support for sites offering interventional cardiac catheterization. The data show that sites offering the intervention without a surgeon achieve better results that sites that ship patients out for the interventions, and that the risk without on-site thoracic surgery backup is negligible.
AHA, ACC Change in requirement for surgical support: Class IIb -> Class IIa Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, level of Evidence B).
Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC
11.1.2 Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI
Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
11.1.6 Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Medical Therapy alone and had Poor Outcomes
11.2.8 CABG: a Superior Revascularization Modality to PCI in Patients with poor LVF, Multivessel disease and Diabetes, Similar Risk of Stroke between 31 days and 5 years, post intervention
The following paper in Cells describes the discovery of protein interactors of endoglin, which is recruited to membranes at the TGF-β receptor complex upon TGF-β signaling. Interesting a carbohydrate binding protein, galectin-3, and an E3-ligase, TRIM21, were found to be unique interactors within this complex.
Gallardo-Vara E, Ruiz-Llorente L, Casado-Vela J, Ruiz-Rodríguez MJ, López-Andrés N, Pattnaik AK, Quintanilla M, Bernabeu C. Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners. Cells. 2019 Sep 13;8(9):1082. doi: 10.3390/cells8091082. PMID: 31540324; PMCID: PMC6769930.
Abstract
Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.
Endoglin is an auxiliary TGF-β co-receptor predominantly expressed in endothelial cells, which is involved in vascular development, repair, homeostasis, and disease [1,2,3,4]. Heterozygous mutations in the human ENDOGLIN gene (ENG) cause hereditary hemorrhagic telangiectasia (HHT) type 1, a vascular disease associated with nasal and gastrointestinal bleeds, telangiectases on skin and mucosa and arteriovenous malformations in the lung, liver, and brain [4,5,6]. The key role of endoglin in the vasculature is also illustrated by the fact that endoglin-KO mice die in utero due to defects in the vascular system [7]. Endoglin expression is markedly upregulated in proliferating endothelial cells involved in active angiogenesis, including the solid tumor neovasculature [8,9]. For this reason, endoglin has become a promising target for the antiangiogenic treatment of cancer [10,11,12]. Endoglin is also expressed in cancer cells where it can behave as both a tumor suppressor in prostate, breast, esophageal, and skin carcinomas [13,14,15,16] and a promoter of malignancy in melanoma and Ewing’s sarcoma [17]. Ectodomain shedding of membrane-bound endoglin may lead to a circulating form of the protein, also known as soluble endoglin (sEng) [18,19,20]. Increased levels of sEng have been found in several vascular-related pathologies, including preeclampsia, a disease of high prevalence in pregnant women which, if left untreated, can lead to serious and even fatal complications for both mother and baby [2,18,19,21]. Interestingly, several lines of evidence support a pathogenic role of sEng in the vascular system, including endothelial dysfunction, antiangiogenic activity, increased vascular permeability, inflammation-associated leukocyte adhesion and transmigration, and hypertension [18,22,23,24,25,26,27]. Because of its key role in vascular pathology, a large number of studies have addressed the structure and function of endoglin at the molecular level, in order to better understand its mechanism of action.
Galectin-3 Interacts with Endoglin in Cells
Galectin-3 is a secreted member of the lectin family with the capacity to bind membrane glycoproteins like endoglin and is involved in the pathogenesis of many human diseases [52]. We confirmed the protein screen data for galectin-3, as evidenced by two-way co-immunoprecipitation of endoglin and galectin-3 upon co-transfection in CHO-K1 cells. As shown in Figure 1A, galectin-3 and endoglin were efficiently transfected, as demonstrated by Western blot analysis in total cell extracts. No background levels of endoglin were observed in control cells transfected with the empty vector (Ø). By contrast, galectin-3 could be detected in all samples but, as expected, showed an increased signal in cells transfected with the galectin-3 expression vector. Co-immunoprecipitation studies of these cell lysates showed that galectin-3 was present in endoglin immunoprecipitates (Figure 1B). Conversely, endoglin was also detected in galectin-3 immunoprecipitates (Figure 1C).
Figure 1. Protein–protein association between galectin-3 and endoglin. (A–C). Co-immunoprecipitation of galectin-3 and endoglin. CHO-K1 cells were transiently transfected with pcEXV-Ø (Ø), pcEXV–HA–EngFL (Eng) and pcDNA3.1–Gal-3 (Gal3) expression vectors. (A) Total cell lysates (TCL) were analyzed by SDS-PAGE under reducing conditions, followed by Western blot (WB) analysis using specific antibodies to endoglin, galectin-3 and β-actin (loading control). Cell lysates were subjected to immunoprecipitation (IP) with anti-endoglin (B) or anti-galectin-3 (C) antibodies, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin or anti-galectin-3 antibodies, as indicated. Negative controls with an IgG2b (B) and IgG1 (C) were included. (D) Protein-protein interactions between galectin-3 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 7.3 µM recombinant human galectin-3/6xHis at the C-terminus (LGALS3), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.
Figure 2.Galectin-3 and endoglin co-localize in human endothelial cells. Human umbilical vein-derived endothelial cell (HUVEC) monolayers were fixed with paraformaldehyde, permeabilized with Triton X-100, incubated with the mouse mAb P4A4 anti-endoglin, washed, and incubated with a rabbit polyclonal anti-galectin-3 antibody (PA5-34819). Galectin-3 and endoglin were detected by immunofluorescence upon incubation with Alexa 647 goat anti-rabbit IgG (red staining) and Alexa 488 goat anti-mouse IgG (green staining) secondary antibodies, respectively. (A) Single staining of galectin-3 (red) and endoglin (green) at the indicated magnifications. (B) Merge images plus DAPI (nuclear staining in blue) show co-localization of galectin-3 and endoglin (yellow color). Representative images of five different experiments are shown.
Endoglin associates with the cullin-type E3 ligase TRIM21
Figure 3.Protein–protein association between TRIM21 and endoglin. (A–E) Co-immunoprecipitation of TRIM21 and endoglin. A,B. HUVEC monolayers were lysed and total cell lysates (TCL) were subjected to SDS-PAGE under reducing (for TRIM21 detection) or nonreducing (for endoglin detection) conditions, followed by Western blot (WB) analysis using antibodies to endoglin, TRIM21 or β-actin (A). HUVECs lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or negative control antibodies, followed by WB analysis with anti-endoglin (B). C,D. CHO-K1 cells were transiently transfected with pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (E) or pcDNA3.1–HA–hTRIM21 (T) expression vectors, as indicated. Total cell lysates (TCL) were subjected to SDS-PAGE under nonreducing conditions and WB analysis using specific antibodies to endoglin, TRIM21, and β-actin (C). Cell lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or anti-endoglin antibodies, followed by SDS-PAGE under reducing (upper panel) or nonreducing (lower panel) conditions and WB analysis with anti-TRIM21 or anti-endoglin antibodies. Negative controls of appropriate IgG were included (D). E. CHO-K1 cells were transiently transfected with pcDNA3.1–HA–hTRIM21 and pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (FL; full-length), pDisplay–HA–EngEC (EC; cytoplasmic-less) or pDisplay–HA–EngTMEC (TMEC; cytoplasmic-less) expression vectors, as indicated. Cell lysates were subjected to immunoprecipitation with anti-TRIM21, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin antibodies, as indicated. The asterisk indicates the presence of a nonspecific band. Mr, molecular reference; Eng, endoglin; TRIM, TRIM21. (F) Protein–protein interactions between TRIM21 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 5.4 µM recombinant human TRIM21/6xHis at the N-terminus (R052), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.
Table 1. Human protein-array analysis of endoglin interactors1.
1 Microarrays containing over 9000 unique human proteins were screened using recombinant sEng as a probe. Protein interactors showing the highest scores (Z-score ≥2.0) are listed. GeneBank (https://www.ncbi.nlm.nih.gov/genbank/) and UniProtKB (https://www.uniprot.org/help/uniprotkb) accession numbers are indicated with a yellow or green background, respectively. The cellular compartment of each protein was obtained from the UniProtKB webpage. Proteins selected for further studies (TRIM21 and galectin-3) are indicated in bold type with blue background.
Note: the following are from NCBI Genbank and Genecards on TRIM21
Official Symbol TRIM21provided by HGNC Official Full Name tripartite motif containing 21provided by HGNC Primary source HGNC:HGNC:11312 See related Ensembl:ENSG00000132109MIM:109092;AllianceGenome:HGNC:11312 Gene type protein coding RefSeq status REVIEWED Organism Homo sapiens Lineage Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo Also known as SSA; RO52; SSA1; RNF81; Ro/SSA Summary This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008] Expression Ubiquitous expression in spleen (RPKM 15.5), appendix (RPKM 13.2) and 24 other tissues See more Orthologs mouseall NEW Try the new Gene table Try the new Transcript table
This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses (PubMed:26347139, 16297862, 16316627, 16472766, 16880511, 18022694, 18361920, 18641315, 18845142, 19675099). Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through ‘Lys-63’-linked ubiquitination of NMI (PubMed:26342464). ( RO52_HUMAN,P19474 )
Molecular function for TRIM21 Gene according to UniProtKB/Swiss-Prot
Function:
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression.
Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners
Gallardo-Vara E, Ruiz-Llorente L, Casado-Vela J, Ruiz-Rodríguez MJ, López-Andrés N, Pattnaik AK, Quintanilla M, Bernabeu C. Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners. Cells. 2019 Sep 13;8(9):1082. doi: 10.3390/cells8091082. PMID: 31540324; PMCID: PMC6769930.
Abstract
Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.
Endoglin is an auxiliary TGF-β co-receptor predominantly expressed in endothelial cells, which is involved in vascular development, repair, homeostasis, and disease [1,2,3,4]. Heterozygous mutations in the human ENDOGLIN gene (ENG) cause hereditary hemorrhagic telangiectasia (HHT) type 1, a vascular disease associated with nasal and gastrointestinal bleeds, telangiectases on skin and mucosa and arteriovenous malformations in the lung, liver, and brain [4,5,6]. The key role of endoglin in the vasculature is also illustrated by the fact that endoglin-KO mice die in utero due to defects in the vascular system [7]. Endoglin expression is markedly upregulated in proliferating endothelial cells involved in active angiogenesis, including the solid tumor neovasculature [8,9]. For this reason, endoglin has become a promising target for the antiangiogenic treatment of cancer [10,11,12]. Endoglin is also expressed in cancer cells where it can behave as both a tumor suppressor in prostate, breast, esophageal, and skin carcinomas [13,14,15,16] and a promoter of malignancy in melanoma and Ewing’s sarcoma [17]. Ectodomain shedding of membrane-bound endoglin may lead to a circulating form of the protein, also known as soluble endoglin (sEng) [18,19,20]. Increased levels of sEng have been found in several vascular-related pathologies, including preeclampsia, a disease of high prevalence in pregnant women which, if left untreated, can lead to serious and even fatal complications for both mother and baby [2,18,19,21]. Interestingly, several lines of evidence support a pathogenic role of sEng in the vascular system, including endothelial dysfunction, antiangiogenic activity, increased vascular permeability, inflammation-associated leukocyte adhesion and transmigration, and hypertension [18,22,23,24,25,26,27]. Because of its key role in vascular pathology, a large number of studies have addressed the structure and function of endoglin at the molecular level, in order to better understand its mechanism of action.
Galectin-3 Interacts with Endoglin in Cells
Galectin-3 is a secreted member of the lectin family with the capacity to bind membrane glycoproteins like endoglin and is involved in the pathogenesis of many human diseases [52]. We confirmed the protein screen data for galectin-3, as evidenced by two-way co-immunoprecipitation of endoglin and galectin-3 upon co-transfection in CHO-K1 cells. As shown in Figure 1A, galectin-3 and endoglin were efficiently transfected, as demonstrated by Western blot analysis in total cell extracts. No background levels of endoglin were observed in control cells transfected with the empty vector (Ø). By contrast, galectin-3 could be detected in all samples but, as expected, showed an increased signal in cells transfected with the galectin-3 expression vector. Co-immunoprecipitation studies of these cell lysates showed that galectin-3 was present in endoglin immunoprecipitates (Figure 1B). Conversely, endoglin was also detected in galectin-3 immunoprecipitates (Figure 1C).
Figure 1. Protein–protein association between galectin-3 and endoglin. (A–C). Co-immunoprecipitation of galectin-3 and endoglin. CHO-K1 cells were transiently transfected with pcEXV-Ø (Ø), pcEXV–HA–EngFL (Eng) and pcDNA3.1–Gal-3 (Gal3) expression vectors. (A) Total cell lysates (TCL) were analyzed by SDS-PAGE under reducing conditions, followed by Western blot (WB) analysis using specific antibodies to endoglin, galectin-3 and β-actin (loading control). Cell lysates were subjected to immunoprecipitation (IP) with anti-endoglin (B) or anti-galectin-3 (C) antibodies, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin or anti-galectin-3 antibodies, as indicated. Negative controls with an IgG2b (B) and IgG1 (C) were included. (D) Protein-protein interactions between galectin-3 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 7.3 µM recombinant human galectin-3/6xHis at the C-terminus (LGALS3), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.
Figure 2.Galectin-3 and endoglin co-localize in human endothelial cells. Human umbilical vein-derived endothelial cell (HUVEC) monolayers were fixed with paraformaldehyde, permeabilized with Triton X-100, incubated with the mouse mAb P4A4 anti-endoglin, washed, and incubated with a rabbit polyclonal anti-galectin-3 antibody (PA5-34819). Galectin-3 and endoglin were detected by immunofluorescence upon incubation with Alexa 647 goat anti-rabbit IgG (red staining) and Alexa 488 goat anti-mouse IgG (green staining) secondary antibodies, respectively. (A) Single staining of galectin-3 (red) and endoglin (green) at the indicated magnifications. (B) Merge images plus DAPI (nuclear staining in blue) show co-localization of galectin-3 and endoglin (yellow color). Representative images of five different experiments are shown.
Endoglin associates with the cullin-type E3 ligase TRIM21
Figure 3.Protein–protein association between TRIM21 and endoglin. (A–E) Co-immunoprecipitation of TRIM21 and endoglin. A,B. HUVEC monolayers were lysed and total cell lysates (TCL) were subjected to SDS-PAGE under reducing (for TRIM21 detection) or nonreducing (for endoglin detection) conditions, followed by Western blot (WB) analysis using antibodies to endoglin, TRIM21 or β-actin (A). HUVECs lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or negative control antibodies, followed by WB analysis with anti-endoglin (B). C,D. CHO-K1 cells were transiently transfected with pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (E) or pcDNA3.1–HA–hTRIM21 (T) expression vectors, as indicated. Total cell lysates (TCL) were subjected to SDS-PAGE under nonreducing conditions and WB analysis using specific antibodies to endoglin, TRIM21, and β-actin (C). Cell lysates were subjected to immunoprecipitation (IP) with anti-TRIM21 or anti-endoglin antibodies, followed by SDS-PAGE under reducing (upper panel) or nonreducing (lower panel) conditions and WB analysis with anti-TRIM21 or anti-endoglin antibodies. Negative controls of appropriate IgG were included (D). E. CHO-K1 cells were transiently transfected with pcDNA3.1–HA–hTRIM21 and pDisplay–HA–Mock (Ø), pDisplay–HA–EngFL (FL; full-length), pDisplay–HA–EngEC (EC; cytoplasmic-less) or pDisplay–HA–EngTMEC (TMEC; cytoplasmic-less) expression vectors, as indicated. Cell lysates were subjected to immunoprecipitation with anti-TRIM21, followed by SDS-PAGE under reducing conditions and WB analysis with anti-endoglin antibodies, as indicated. The asterisk indicates the presence of a nonspecific band. Mr, molecular reference; Eng, endoglin; TRIM, TRIM21. (F) Protein–protein interactions between TRIM21 and endoglin using Bio-layer interferometry (BLItz). The Ni–NTA biosensors tips were loaded with 5.4 µM recombinant human TRIM21/6xHis at the N-terminus (R052), and protein binding was measured against 0.1% BSA in PBS (negative control) or 4.1 µM soluble endoglin (sEng). Kinetic sensorgrams were obtained using a single channel ForteBioBLItzTM instrument.
Table 1. Human protein-array analysis of endoglin interactors1.
1 Microarrays containing over 9000 unique human proteins were screened using recombinant sEng as a probe. Protein interactors showing the highest scores (Z-score ≥2.0) are listed. GeneBank (https://www.ncbi.nlm.nih.gov/genbank/) and UniProtKB (https://www.uniprot.org/help/uniprotkb) accession numbers are indicated with a yellow or green background, respectively. The cellular compartment of each protein was obtained from the UniProtKB webpage. Proteins selected for further studies (TRIM21 and galectin-3) are indicated in bold type with blue background.
Note: the following are from NCBI Genbank and Genecards on TRIM21
This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]
Expression
Ubiquitous expression in spleen (RPKM 15.5), appendix (RPKM 13.2) and 24 other tissues See more
This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses (PubMed:26347139, 16297862, 16316627, 16472766, 16880511, 18022694, 18361920, 18641315, 18845142, 19675099). Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through ‘Lys-63’-linked ubiquitination of NMI (PubMed:26342464). ( RO52_HUMAN,P19474 )
Molecular function for TRIM21 Gene according to UniProtKB/Swiss-Prot
Function:
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression.
Other Articles in this Open Access Scientific Journal on Galectins and Proteosome Include
Parasym™ neuromodulation device reveals promising developments in the treatment of heart failure patients with preserved ejection fraction: Clinical Trial Results
Reporter and Curator: Aviva Lev-Ari, PhD, RN
Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction: A Pilot Randomized Clinical Trial
A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction. Low‐level transcutaneous vagus nerve stimulation suppresses inflammation in humans. We conducted a sham‐controlled, double‐blind, randomized clinical trial to examine the effect of chronic low‐level transcutaneous vagus nerve stimulation on cardiac function, exercise capacity, and inflammation in patients with heart failure with preserved ejection fraction.
Methods and Results
Patients with heart failure with preserved ejection fraction and at least 2 additional comorbidities (obesity, diabetes, hypertension, or age ≥65 years) were randomized to either active (tragus) or sham (earlobe) low‐level transcutaneous vagus nerve stimulation (20 Hz, 1 mA below discomfort threshold), for 1 hour daily for 3 months. Echocardiography, 6‐minute walk test, quality of life, and serum cytokines were assessed at baseline and 3 months. Fifty‐two patients (mean age 70.4±9.2 years; 70% female) were included (active, n=26; sham, n=26). Baseline characteristics were balanced between the 2 arms. Adherence to the protocol of daily stimulation was >90% in both arms (P>0.05). While the early mitral inflow Doppler velocity to the early diastolic mitral annulus velocity ratio did not differ between groups, global longitudinal strain and tumor necrosis factor‐α levels at 3 months were significantly improved in the active compared with the sham arm (−18.6%±2.5% versus −16.0%±2.4%, P=0.002; 8.9±2.8 pg/mL versus 11.3±2.9 pg/mL, P=0.007, respectively). The reduction in tumor necrosis factor‐α levels correlated with global longitudinal strain improvement (r=−0.73, P=0.001). Quality of life was better in the active arm. No device‐related side effects were observed.
Conclusions
Neuromodulation with low‐level transcutaneous vagus nerve stimulation over 3 months resulted in a significant improvement in global longitudinal strain, inflammatory cytokines, and quality of life in patients with heart failure with preserved ejection fraction.
Press Release Announcement by Parasym™ is a neurotechnology company dedicated to shaping the future of bioelectric medicine. Founded in 2015 by Sophie and Nathan Dundovic, is focused on providing innovative neuromodulation products that restore health. The company has over 60 clinical partnerships across 4 continents, and over 1,000,000 treatment sessions completed. For more information about Parasym™’s latest products, visit nurosym.com
Parasym™ is the only company to have developed a device that utilises advances in electroceutical technology to provide ground-breaking non-invasive treatment for numerous health and wellness conditions ranging from mental to physical health including heart failure, without the need for heart failure medication. For further information about Parasym™ visit parasym.co.
The neuromodulation device is non-invasive, patients are able to use it in addition to medication should they want to. Electroceuticals are set to revolutionise the treatment paradigm in heart failure, especially neuromodulation with its capacity to provide highly targeted treatment without drug interaction or side effects.
Clinical trial results
The study revealed significant improvements in levels of proinflammatory cytokines Interleukin-8 and Tumour Necrosis Factor alpha, indicating that the treatment had a significant anti-inflammatory effect, as well as in global longitudinal strain, a core indicator of cardiac mechanics.
Dr Stavros Stavrakis MD, PhD, Associate Professor at University of Oklahoma College of Medicine commented: “We conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low-level transcutaneous vagus nerve stimulation on cardiac function, exercise capacity, and inflammation in a subgroup of patients with heart failure with preserved ejection fraction with a predominantly inflammatory-metabolic phenotype. In this patient population, neuromodulation with low-level transcutaneous vagus nerve stimulation over three months resulted in a significant improvement in global longitudinal strain, inflammatory cytokines, and quality of life. Our results support the emerging paradigm of noninvasive neuromodulation to treat selected patients with heart failure with preserved ejection fraction and provide the basis for further randomized trials.”
Parasym™️ is committed to supporting groundbreaking cardiac research and we are working to bring non-invasive electroceutical treatments to patients suffering from heart failure.
“The results published in the Journal of the American Heart Association highlight the brilliant work done by researchers at the University of Oklahoma and show the incredible potential that Parasym’s neuromodulatory technology can have in a condition where there is an urgent unmet clinical need for new treatment options. We are incredibly proud of the trial results and hope to continue to demonstrate the positive impact of neuromodulation in healthcare.”
SOURCE
From: Sofia Leadbetter <sofia@lem-uhn.com> Date: Tuesday, February 22, 2022 at 9:56 AM To: Aviva Lev-Ari <avivalev-ari@alum.berkeley.edu> Subject: Re: A groundbreaking clinical trial using Parasym™ neuromodulation device reveals promising developments in the treatment of heart failure
Other related articles published in this Open Access Online Scientific Journal includes the following:
I. A related topic is Renal denervation for Hypertension control by a medical device
Single-Author Reporting on MedTech and Cardiac Medical Devices by
Experimental Therapy (Left inter-atrial shunt implant device) for Heart Failure: Expert Opinion on a Preliminary Study on Heart Failure with preserved Ejection Fraction
This book is a comprehensive review of Nitric Oxide, its discovery, function, and related opportunities for Targeted Therapy written by Experts, Authors, Writers: PhDs, MDs, MD/PhDs, PharmDs. Nitric oxide plays a wide variety of roles in cardiovascular system and acts as a central point for signal transduction pathway in endothelium. NITRIC OXIDE modulates vascular tone, fibrinolysis, blood pressure and proliferation of vascular smooth muscle cells. In the cardiovascular system disruption of NITRIC OXIDE pathways or alterations in NITRIC OXIDE production can result in predisposition to hypertension, hypercholesterolemia, diabetes mellitus, atherosclerosis and thrombosis. The essential role of NITRIC OXIDE is seen widely in organ function and in disease development. The role of NITRIC OXIDE covers the cardiovascular system, the acuity of sepsis and septic shock, gastrointestinal disease, renal disease, and neurological disorders. The final chapter is the essential role of NITRIC OXIDE in carcinogenesis. Therapeutic Targets to Clinical Applications: Pharmaco-therapy was developed and it represents methods to induce the production of Nitric Oxide and its enzymes for novel combination drug therapies.
This e-Book is a comprehensive review of recent Original Research on Cardiovascular Diseases: Causes, Risks and Management and related opportunities for Targeted Therapy written by Experts, Authors and Writers. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012. Topics covered in greater details include: •Alternative solutions in Treatment of Heart Failure (HF), medical devices, biomarkers and agent efficacy are handled all in one chapter. •PCI for valves vs Open heart Valve replacement •PDA and Complications of Surgery — only curation could create the picture of this unique combination of debate, as exemplified of Endarterectomy (CEA) vs Stenting the Carotid Artery (CAS), ischemic leg, renal artery stenosis.
This e-Book is a comprehensive review of recent Original Research on Cardiovascular Diseases: Causes, Risks and Management and related opportunities for Targeted Therapy written by Experts, Authors and Writers. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012. This e-Book includes a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals. The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA). The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA).
This e-Book is a comprehensive review of recent Original Research on Cardiovascular Diseases: Causes, Risks and Management and related opportunities for Targeted Therapy written by Experts, Authors and Writers. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012. Part 1 is concerned with Posttranslational Modification of Proteins, vital for understanding cellular regulation and dysregulation. Part 2 is concerned with Translational Medical Therapeutics, the efficacy of medical and surgical decisions based on bringing the knowledge gained from the laboratory, and from clinical trials into the realm opf best practice. The time for this to occur in practice in the past has been through roughly a generation of physicians. That was in part related to the busy workload of physicians, and inability to easily access specialty literature as the volume and complexity increased. This had an effect of making access of a family to a primary care provider through a lifetime less likely than the period post WWII into the 1980s.
Pharmacologic therapy represents the dominant strategy for management of cardiovascular disease and consequences, deferring, complementing and often supplanting structural and functional interventions. The general strategy of medical management is to identify the biochemicals that control cardiovascular functions and responses, identify the consequences of push and pull (stimulation, potentiation, inhibition, blockade, counteractivity), check benefits and harm, systematically document the impact, both in population studies and in individuals, make wise choices, and optimize dosing. Medications mimic or modify natural biologic activities. Therefore genomics (the study of gene products, especially, messengers and receptors) and the cascade of signaling pathways that modulate responses identifies the myriad but theoretically finite possibilities for chemical intervention. Often there are many pathways that affect or are affected by cardiovascular disease, and multiple ways to promote desirable changes. Elucidation of the biochemical signal changes that correspond to or respond to cardiovascular disease conditions and treatments provides both biomarkers of patient health status and targets for therapy. The process of homeostasis resists change, including resisting desirable changes that aim to correct maladaptive biology. Thus medication to block an excess in heart rate and blood pressure, for example, leads to upregulation in the number and sensitivity of blocked receptors as well changes in activity of sibling pathways, which mitigate the impact of the blocking medication and promote rebound worsening of the primary concern if the medication gets interrupted. These issues influence combination therapy choices as well as concern about compliance with prescriptions. Therefore this guided tour of curated data relating to medical management of cardiovascular diseases draws from the human genome project to identify treatment opportunities, pathophysiology to understand the impact of disease and maladaptive responses, clinical disease and pharmaceutical classifications, and clinical trial results to clarify expected outcomes. Curation also addresses context, insight and opportunity. Review of all of the above by teams of experts leads to formulation of guidelines, but each patient is a unique individual for whom customized optimization offers further benefits. Optimal care requires understanding of all of the above to guide and optimize the offering and patient education for wise choices promoting optimal quality and quantity of life despite the presence of cardiovascular disease. Current health care priorities, current cardiovascular medication classification and offerings, and in depth review of the achievements and limitations of current and anticipated future pharmaceutical therapies for cardiovascular disease are. The current priorities adapt to cost benefit analysis of prevalent cardiovascular disorders, as limited resources are arguably best directed to where they will do the most good. The scope of that concern includes prevention as well as curtailment of severity of impairment, by improving out patient management, aiming at alleviated suffering and achieve sufficient quality of life to avoid expensive hospitalizations, interference with productivity, and shortened lifespan. Major categories of cardiovascular disease are reviewed in separate chapters, based on distinct pathways and therapeutic considerations. The closing chapter addresses adverse effects of therapy. In Part Two we focus on biomarkers – indicators of disease status. Chapter 15 presented recent new examples, such as BNP and high-sensitivity Troponin. Ch.16 addressed how the completion of the mapping of the human genome paves the way for identifying many more biomarkers. Ch.17 reviewed biomarker utility in various disease conditions. Ch.18 reviewed biomarker utility in acute disorders. Ch.19 on cholesterol, lipids, diet and Ch.20 on Inflammation.
In Cardiology, “Interventional” is reserved for procedures that directly produce physical changes. Surgical interventions for cardiovascular diseases include heart or heart and lung transplant, implantation of cardiac assist devices, shock devices and pacemakers, bypass grafts for coronary or other arteries, valve repairs or replacement, removal of plaque (endarterectomy), removal of tumors, and repair or palliation of injuries or of congenital anomalies. All of these interventions are continually studied and improved, with a major effort at minimizing the risk, reducing recovery time and reducing the size of entry scar, for example by use of video scopes instead of direct visualization, and mechanical devices and robotics instead of direct manual access. Interventional Cardiology refers to an often competing non-surgical approach in which access is limited to entry by vein or artery (catheterization). The two teams have joined forces to achieve a major success in replacing aortic valves by femoral artery access without opening the chest at all (TAVR), with on-going progress towards a similar approach to mitral valve replacement. This book addresses disease prevalence, personalized patient and doctor experiences with Cardiac Surgery, the role of transfusion, status of the MedTech market, and a review of major accomplishments from pathology, anesthesiology, radiology, cardiology and surgery. The contributions of specific groups, such as the Texas Heart Institute, the Dalio Institute at New York Presbyterian/Weill Cornell, the Cleveland Clinic, and the Scripps Institute are reviewed. Individual contributions from Eric Topol, Arthur Moss, Paul Zoll, Tim Wu, and Earl E. Bakken (Medtronic co-founder) are included. Discoveries in relevant biology, including ATP (the metabolic paycheck) and plasma metabolomics, and novel technologies such as tethered-liquid perfluorocabon surface biocoating to prevent clotting. Additional curations present views of cardiothoracic surgeons, vascular surgeons and of Catheterization lab interventionists. Business aspects are addressed by review of costs, prevalence, payment methods, prevention impact and business models. Decision support tools are also reviewed, and changes in guidelines. Voices of three Open Heart Surgery Survivors are included. Chapters 4-6 addressed clinical trial data in coronary disease, biomarkers of cardiovascular disorders, coagulation including top roles of nitric oxide, C-reative protein, protein C, aprotinin and thrombin. Chapters 7-8 covered amyloidosis, atherosclerosis, valve disease, flow reserve, atrial fibrillation and roles for advanced imaging. Chapters 9-10 covered unstable angina, transplants, and ventricular assist devices. Chapters 11-14 span interventions on the aorta, peripheral arteries, and coronary arteries, valve surgery and percutaneous valve repair or replacement, plus the growing role of prosthetics and repair by stem cells and tissue engineering. As catheter techniques evolved to compete with bypass surgery they progressed from balloon cracking of obstructive lesions (POBA=plain old balloon angioplasty) to placement of stents (wire fences). Surgeons sometimes use in-stent valves, and now devices analogous to in-stent valves can be placed by catheter for valve replacement in patients with too much co-morbidity to go through heart surgery. Aortic valve replacement by stent (TAVR) has had sufficient success to be considered for all patients who have sufficient impairment to merit intervention. The diameter is large, so a vascular surgeon participates in the arterial access and repair of the access site. Minimally invasive repair of abdominal aorta aneurysm: atherosclerosis offers potentially somewhat protective stiffening of the arterial wall, it can promote clots, athero-emboli, and failure of the remodeling can lead to an outward ballooning, or aneurysm, that promotes both clot formation and wall or lining tears or rupture, cause of sudden death.
2021 Virtual World Medical Innovation Forum, Mass General Brigham, Gene and Cell Therapy, VIRTUAL May 19–21, 2021
The 2021 Virtual World Medical Innovation Forum will focus on the growing impact of gene and cell therapy. Senior healthcare leaders from all over look to shape and debate the area of gene and cell therapy. Our shared belief: no matter the magnitude of change, responsible healthcare is centered on a shared commitment to collaborative innovation–industry, academia, and practitioners working together to improve patients’ lives.
About the World Medical Innovation Forum
Mass General Brigham is pleased to present the World Medical Innovation Forum (WMIF) virtual event Wednesday, May 19 – Friday, May 21. This interactive web event features expert discussions of gene and cell therapy (GCT) and its potential to change the future of medicine through its disease-treating and potentially curative properties. The agenda features 150+ executive speakers from the healthcare industry, venture, startups, life sciences manufacturing, consumer health and the front lines of care, including many Harvard Medical School-affiliated researchers and clinicians. The annual in-person Forum will resume live in Boston in 2022. The World Medical Innovation Forum is presented by Mass General Brigham Innovation, the global business development unit supporting the research requirements of 7,200 Harvard Medical School faculty and research hospitals including Massachusetts General, Brigham and Women’s, Massachusetts Eye and Ear, Spaulding Rehab and McLean Hospital. Follow us on Twitter: twitter.com/@MGBInnovation
Accelerating the Future of Medicine with Gene and Cell Therapy What Comes Next
Co-Chairs identify the key themes of the Forum – set the stage for top GCT opportunities, challenges, and where the field might take medicine in the future. Moderator: Susan Hockfield, PhD
President Emerita and Professor of Neuroscience, MIT
Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT
FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products
payments over time payers and Innovators relations Moderator: Julian Harris, MD
Partner, Deerfield
Promise of CGT realized, what part?
FDA role and interaction in CGT
Manufacturing aspects which is critical Speaker: Dave Lennon, PhD
President, Novartis Gene Therapies
Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT
FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products
payments over time payers and Innovators relations
GCT development for rare diseases is driven by patient and patient-advocate communities. Understanding their needs and perspectives enables biomarker research, the development of value-driving clinical trial endpoints and successful clinical trials. Industry works with patient communities that help identify unmet needs and collaborate with researchers to conduct disease natural history studies that inform the development of biomarkers and trial endpoints. This panel includes patients who have received cutting-edge GCT therapy as well as caregivers and patient advocates. Moderator: Patricia Musolino, MD, PhD
Co-Director Pediatric Stroke and Cerebrovascular Program, MGH
Assistant Professor of Neurology, HMS
What is the Power of One – the impact that a patient can have on their own destiny by participating in Clinical Trials Contacting other participants in same trial can be beneficial Speakers: Jack Hogan
Parkinson patient Constraints by regulatory on participation in clinical trial advance stage is approved participation Patients to determine the level of risk they wish to take Information dissemination is critical Barbara Lavery
Chief Program Officer, ACGT Foundation
Advocacy agency beginning of work Global Genes educational content and out reach to access the information
Patient has the knowledge of the symptoms and recording all input needed for diagnosis by multiple clinicians Early application for CGTDan Tesler
Clinical Trial Patient, BWH/DFCC
Experimental Drug clinical trial patient participation in clinical trial is very important to advance the state of scienceSarah Beth Thomas, RN
Professional Development Manager, BWH
Outcome is unknown, hope for good, support with resources all advocacy groups,
Process at FDA generalize from 1st entry to rules more generalizable Speaker: Peter Marks, MD, PhD
Director, Center for Biologics Evaluation and Research, FDA
Last Spring it became clear that something will work a vaccine by June 2020 belief that enough candidates the challenge manufacture enough and scaling up FDA did not predicted the efficacy of mRNA vaccine vs other approaches expected to work
Recover Work load for the pandemic will wean & clear, Gene Therapies IND application remained flat in the face of the pandemic Rare diseases urgency remains Consensus with industry advisory to get input gene therapy Guidance T-Cell therapy vs Regulation best thinking CGT evolve speedily flexible gained by Guidance
Immune modulators, Immunotherapy Genome editing can make use of viral vectors future technologies nanoparticles and liposome encapsulation
big pharma has portfolios of therapeutics not one drug across Tx areas: cell, gene iodine therapy
collective learning infrastructure features manufacturing at scale early in development Acquisitions strategy for growth # applications for scaling Rick Modi
CEO, Affinia Therapeutics
Copy, paste EDIT from product A to B novel vectors leverage knowledge varient of vector, coder optimization choice of indication is critical exploration on larger populations Speed to R&D and Speed to better gene construct get to clinic with better design vs ASAP
Data sharing clinical experience with vectors strategies patients selection, vector selection, mitigation, patient type specific Louise Rodino-Klapac, PhD
AAV based platform 15 years in development same disease indication vs more than one indication stereotype, analytics as hurdle 1st was 10 years 2nd was 3 years
Safety to clinic vs speed to clinic, difference of vectors to trust
Recent AAV gene therapy product approvals have catalyzed the field. This new class of therapies has shown the potential to bring transformative benefit to patients. With dozens of AAV treatments in clinical studies, all eyes are on the field to gauge its disruptive impact.
The panel assesses the largest challenges of the first two products, the lessons learned for the broader CGT field, and the extent to which they serve as a precedent to broaden the AAV modality.
Is AAV gene therapy restricted to genetically defined disorders, or will it be able to address common diseases in the near term?
Lessons learned from these first-in-class approvals.
Challenges to broaden this modality to similar indications.
Reflections on safety signals in the clinical studies?
Tissue types additional administrations, tech and science, address additional diseases, more science for photoreceptors a different tissue type underlying pathology novelties in last 10 years
Laxterna success to be replicated platform, paradigms measurement visual improved
More science is needed to continue develop vectors reduce toxicity,
AAV can deliver different cargos reduce adverse events improve vectorsRon Philip
Chief Operating Officer, Spark Therapeutics
The first retinal gene therapy, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), was approved by the FDA in 2017.Meredith Schultz, MD
Executive Medical Director, Lead TME, Novartis Gene Therapies
Impact of cell therapy beyond muscular dystrophy, translational medicine, each indication, each disease, each group of patients build platform unlock the promise
Monitoring for Safety signals real world evidence remote markers, home visits, clinical trial made safer, better communication of information
AAV a complex driver in Pharmacology durable, vector of choice, administer in vitro, gene editing tissue specificity, pharmacokinetics side effects and adverse events manufacturability site variation diversify portfolios,
This panel will address the advances in the area of AAV gene therapy delivery looking out the next five years. Questions that loom large are: How can biodistribution of AAV be improved? What solutions are in the wings to address immunogenicity of AAV? Will patients be able to receive systemic redosing of AAV-based gene therapies in the future? What technical advances are there for payload size? Will the cost of manufacturing ever become affordable for ultra-rare conditions? Will non-viral delivery completely supplant viral delivery within the next five years?What are the safety concerns and how will they be addressed? Moderators: Xandra Breakefield, PhD
Ataxia requires therapy targeting multiple organ with one therapy, brain, spinal cord, heart several IND, clinical trials in 2022Mathew Pletcher, PhD
SVP, Head of Gene Therapy Research and Technical Operations, Astellas
Work with diseases poorly understood, collaborations needs example of existing: DMD is a great example explain dystrophin share placedo data
Continue to explore large animal guinea pig not the mice, not primates (ethical issues) for understanding immunogenicity and immune response Manny Simons, PhD
CEO, Akouos
AAV Therapy for the fluid of the inner ear, CGT for the ear vector accessible to surgeons translational work on the inner ear for gene therapy right animal model
Biology across species nerve ending in the cochlea
engineer out of the caspid, lowest dose possible, get desired effect by vector use, 2022 new milestones
The GCT M&A market is booming – many large pharmas have made at least one significant acquisition. How should we view the current GCT M&A market? What is its impact of the current M&A market on technology development? Are these M&A trends new are just another cycle? Has pharma strategy shifted and, if so, what does it mean for GCT companies? What does it mean for patients? What are the long-term prospects – can valuations hold up? Moderator: Adam Koppel, MD, PhD
Managing Director, Bain Capital Life Sciences
What acquirers are looking for??
What is the next generation vs what is real where is the industry going? Speakers:
Debby Baron,
Worldwide Business Development, Pfizer
CGT is an important area Pfizer is active looking for innovators, advancing forward programs of innovation with the experience Pfizer has internally
Scalability and manufacturing regulatory conversations, clinical programs safety in parallel to planning getting drug to patients
ALS – Man 1in 300, Women 1 in 400, next decade increase 7%
10% ALS is heredity 160 pharma in ALS space, diagnosis is late 1/3 of people are not diagnosed, active community for clinical trials Challenges: disease heterogeneity cases of 10 years late in diagnosis. Clinical Trials for ALS in Gene Therapy targeting ASO1 protein therapies FUS gene struck youngsters
Cell therapy for ACTA2 Vasculopathy in the brain and control the BP and stroke – smooth muscle intima proliferation. Viral vector deliver aiming to change platform to non-viral delivery rare disease , gene editing, other mutations of ACTA2 gene target other pathway for atherosclerosis
Oncolytic viruses represent a powerful new technology, but so far an FDA-approved oncolytic (Imlygic) has only occurred in one area – melanoma and that what is in 2015. This panel involves some of the protagonists of this early success story. They will explore why and how Imlygic became approved and its path to commercialization. Yet, no other cancer indications exist for Imlygic, unlike the expansion of FDA-approved indication for immune checkpoint inhibitors to multiple cancers. Why? Is there a limitation to what and which cancers can target? Is the mode of administration a problem?
No other oncolytic virus therapy has been approved since 2015. Where will the next success story come from and why? Will these therapies only be beneficial for skin cancers or other easily accessible cancers based on intratumoral delivery?
The panel will examine whether the preclinical models that have been developed for other cancer treatment modalities will be useful for oncolytic viruses. It will also assess the extent pre-clinical development challenges have slowed the development of OVs. Moderator: Nino Chiocca, MD, PhD
Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH
Harvey W. Cushing Professor of Neurosurgery, HMS
Challenges of manufacturing at Amgen what are they? Speakers: Robert Coffin, PhD
Chief Research & Development Officer, Replimune
2002 in UK promise in oncolytic therapy GNCSF
Phase III melanoma 2015 M&A with Amgen
oncolytic therapy remains non effecting on immune response
data is key for commercialization
do not belief in systemic therapy achieve maximum immune response possible from a tumor by localized injection Roger Perlmutter, MD, PhD
Chairman, Merck & Co.
response rates systemic therapy like PD1, Keytruda, OPTIVA well tolerated combination of Oncolytic with systemic
Physician, Dana Farber-Brigham and Women’s Cancer Center
Assistant Professor of Medicine, HMS
Which person gets oncolytics virus if patient has immune suppression due to other indications
Safety of oncolytic virus greater than Systemic treatment
series biopsies for injected and non injected tissue and compare Suspect of hot tumor and cold tumors likely to have sme response to agent unknown all potential
There are currently two oncolytic virus products on the market, one in the USA and one in China. As of late 2020, there were 86 clinical trials 60 of which were in phase I with just 2 in Phase III the rest in Phase I/II or Phase II. Although global sales of OVs are still in the ramp-up phase, some projections forecast OVs will be a $700 million market by 2026. This panel will address some of the major questions in this area:
What regulatory challenges will keep OVs from realizing their potential? Despite the promise of OVs for treating cancer only one has been approved in the US. Why has this been the case? Reasons such have viral tropism, viral species selection and delivery challenges have all been cited. However, these are also true of other modalities. Why then have oncolytic virus approaches not advanced faster and what are the primary challenges to be overcome?
Will these need to be combined with other agents to realize their full efficacy and how will that impact the market?
Why are these companies pursuing OVs while several others are taking a pass?
In 2020 there were a total of 60 phase I trials for Oncolytic Viruses. There are now dozens of companies pursuing some aspect of OV technology. This panel will address:
How are small companies equipped to address the challenges of developing OV therapies better than large pharma or biotech?
Will the success of COVID vaccines based on Adenovirus help the regulatory environment for small companies developing OV products in Europe and the USA?
Is there a place for non-viral delivery and other immunotherapy companies to engage in the OV space? Would they bring any real advantages?
Systemic delivery Oncolytic Virus IV delivery woman in remission
Collaboration with Regeneron
Data collection: Imageable reporter secretable reporter, gene expression
Field is intense systemic oncolytic delivery is exciting in mice and in human, response rates are encouraging combination immune stimulant, check inhibitors
Few areas of potential cancer therapy have had the attention and excitement of CAR-T. This panel of leading executives, developers, and clinician-scientists will explore the current state of CAR-T and its future prospects. Among the questions to be addressed are:
Is CAR-T still an industry priority – i.e. are new investments being made by large companies? Are new companies being financed? What are the trends?
What have we learned from first-generation products, what can we expect from CAR-T going forward in novel targets, combinations, armored CAR’s and allogeneic treatment adoption?
Early trials showed remarkable overall survival and progression-free survival. What has been observed regarding how enduring these responses are?
Most of the approvals to date have targeted CD19, and most recently BCMA. What are the most common forms of relapses that have been observed?
Is there a consensus about what comes after these CD19 and BCMA trials as to additional targets in liquid tumors? How have dual-targeted approaches fared?
The potential application of CAR-T in solid tumors will be a game-changer if it occurs. The panel explores the prospects of solid tumor success and what the barriers have been. Questions include:
How would industry and investor strategy for CAR-T and solid tumors be characterized? Has it changed in the last couple of years?
Does the lack of tumor antigen specificity in solid tumors mean that lessons from liquid tumor CAR-T constructs will not translate well and we have to start over?
Whether due to antigen heterogeneity, a hostile tumor micro-environment, or other factors are some specific solid tumors more attractive opportunities than others for CAR-T therapy development?
Given the many challenges that CAR-T faces in solid tumors, does the use of combination therapies from the start, for example, to mitigate TME effects, offer a more compelling opportunity.
Executive Director, Head of Cell Therapy Research, Exploratory Immuno-Oncology, NIBR
2017 CAR-T first approval
M&A and research collaborations
TCR tumor specific antigens avoid tissue toxicity Knut Niss, PhD
CTO, Mustang Bio
tumor hot start in 12 month clinical trial solid tumors , theraties not ready yet. Combination therapy will be an experimental treatment long journey checkpoint inhibitors to be used in combination maintenance Lipid tumor Barbra Sasu, PhD
CSO, Allogene
T cell response at prostate cancer
tumor specific
cytokine tumor specific signals move from solid to metastatic cell type for easier infiltration
Where we might go: safety autologous and allogeneic Jay Short, PhD
Chairman, CEO, Cofounder, BioAlta, Inc.
Tumor type is not enough for development of therapeutics other organs are involved in the periphery
difficult to penetrate solid tumors biologics activated in the tumor only, positive changes surrounding all charges, water molecules inside the tissue acidic environment target the cells inside the tumor and not outside
The modes of GCT manufacturing have the potential of fundamentally reordering long-established roles and pathways. While complexity goes up the distance from discovery to deployment shrinks. With the likelihood of a total market for cell therapies to be over $48 billion by 2027, groups of products are emerging. Stem cell therapies are projected to be $28 billion by 2027 and non-stem cell therapies such as CAR-T are projected be $20 billion by 2027. The manufacturing challenges for these two large buckets are very different. Within the CAR-T realm there are diverging trends of autologous and allogeneic therapies and the demands on manufacturing infrastructure are very different. Questions for the panelists are:
Help us all understand the different manufacturing challenges for cell therapies. What are the trade-offs among storage cost, batch size, line changes in terms of production cost and what is the current state of scaling naïve and stem cell therapy treatment vs engineered cell therapies?
For cell and gene therapy what is the cost of Quality Assurance/Quality Control vs. production and how do you think this will trend over time based on your perspective on learning curves today?
Will point of care production become a reality? How will that change product development strategy for pharma and venture investors? What would be the regulatory implications for such products?
How close are allogeneic CAR-T cell therapies? If successful what are the market implications of allogenic CAR-T? What are the cost implications and rewards for developing allogeneic cell therapy treatments?
Global Head of Product Development, Gene & Cell Therapy, Catalent
2/3 autologous 1/3 allogeneic CAR-T high doses and high populations scale up is not done today quality maintain required the timing logistics issues centralized vs decentralized allogeneic are health donors innovations in cell types in use improvements in manufacturing
China embraced gene and cell therapies early. The first China gene therapy clinical trial was in 1991. China approved the world’s first gene therapy product in 2003—Gendicine—an oncolytic adenovirus for the treatment of advanced head and neck cancer. Driven by broad national strategy, China has become a hotbed of GCT development, ranking second in the world with more than 1,000 clinical trials either conducted or underway and thousands of related patents. It has a booming GCT biotech sector, led by more than 45 local companies with growing IND pipelines.
In late 1990, a T cell-based immunotherapy, cytokine-induced killer (CIK) therapy became a popular modality in the clinic in China for tumor treatment. In early 2010, Chinese researchers started to carry out domestic CAR T trials inspired by several important reports suggested the great antitumor function of CAR T cells. Now, China became the country with the most registered CAR T trials, CAR T therapy is flourishing in China.
The Chinese GCT ecosystem has increasingly rich local innovation and growing complement of development and investment partnerships – and also many subtleties.
This panel, consisting of leaders from the China GCT corporate, investor, research and entrepreneurial communities, will consider strategic questions on the growth of the gene and cell therapy industry in China, areas of greatest strength, evolving regulatory framework, early successes and products expected to reach the US and world market. Moderator: Min Wu, PhD
Managing Director, Fosun Health Fund
What are the area of CGT in China, regulatory similar to the US Speakers: Alvin Luk, PhD
CEO, Neuropath Therapeutics
Monogenic rare disease with clear genomic target
Increase of 30% in patient enrollment
Regulatory reform approval is 60 days no delayPin Wang, PhD
CSO, Jiangsu Simcere Pharmaceutical Co., Ltd.
Similar starting point in CGT as the rest of the World unlike a later starting point in other biologicalRichard Wang, PhD
CEO, Fosun Kite Biotechnology Co., Ltd
Possibilities to be creative and capitalize the new technologies for innovating drug
Support of the ecosystem by funding new companie allowing the industry to be developed in China
Autologous in patients differences cost challengeTian Xu, PhD
Vice President, Westlake University
ICH committee and Chinese FDA -r regulation similar to the US
Difference is the population recruitment, in China patients are active participants in skin disease
Active in development of transposome
Development of non-viral methods, CRISPR still in D and transposome
In China price of drugs regulatory are sensitive Shunfei Yan, PhD
The COVID vaccine race has propelled mRNA to the forefront of biomedicine. Long considered as a compelling modality for therapeutic gene transfer, the technology may have found its most impactful application as a vaccine platform. Given the transformative industrialization, the massive human experience, and the fast development that has taken place in this industry, where is the horizon? Does the success of the vaccine application, benefit or limit its use as a therapeutic for CGT?
How will the COVID success impact the rest of the industry both in therapeutic and prophylactic vaccines and broader mRNA lessons?
How will the COVID success impact the rest of the industry both on therapeutic and prophylactic vaccines and broader mRNA lessons?
Beyond from speed of development, what aspects make mRNA so well suited as a vaccine platform?
Will cost-of-goods be reduced as the industry matures?
How does mRNA technology seek to compete with AAV and other gene therapy approaches?
Many years of mRNA pivoting for new diseases, DARPA, nucleic Acids global deployment of a manufacturing unit on site where the need arise Elan Musk funds new directions at Moderna
How many mRNA can be put in one vaccine: Dose and tolerance to achieve efficacy
45 days for Personalized cancer vaccine one per patient
Hemophilia has been and remains a hallmark indication for the CGT. Given its well-defined biology, larger market, and limited need for gene transfer to provide therapeutic benefit, it has been at the forefront of clinical development for years, however, product approval remains elusive. What are the main hurdles to this success? Contrary to many indications that CGT pursues no therapeutic options are available to patients, hemophiliacs have an increasing number of highly efficacious treatment options. How does the competitive landscape impact this field differently than other CGT fields? With many different players pursuing a gene therapy option for hemophilia, what are the main differentiators? Gene therapy for hemophilia seems compelling for low and middle-income countries, given the cost of currently available treatments; does your company see opportunities in this market? Moderator: Nancy Berliner, MD
Safety concerns, high burden of treatment CGT has record of safety and risk/benefit adoption of Tx functional cure CGT is potent Tx relative small quantity of protein needs be delivered
Potency and quality less quantity drug and greater potency
risk of delivery unwanted DNA, capsules are critical
analytics is critical regulator involvement in potency definition
Director, Center for Rare Neurological Diseases, MGH
Associate Professor, Neurology, HMS
Single gene disorder NGS enable diagnosis, DIagnosis to Treatment How to know whar cell to target, make it available and scale up Address gap: missing components Biomarkers to cell types lipid chemistry cell animal biology
crosswalk from bone marrow matter
New gene discovered that causes neurodevelopment of stagnant genes Examining new Biology cell type specific biomarkers
The American Diabetes Association estimates 30 million Americans have diabetes and 1.5 million are diagnosed annually. GCT offers the prospect of long-sought treatment for this enormous cohort and their chronic requirements. The complexity of the disease and its management constitute a grand challenge and highlight both the potential of GCT and its current limitations.
Islet transplantation for type 1 diabetes has been attempted for decades. Problems like loss of transplanted islet cells due to autoimmunity and graft site factors have been difficult to address. Is there anything different on the horizon for gene and cell therapies to help this be successful?
How is the durability of response for gene or cell therapies for diabetes being addressed? For example, what would the profile of an acceptable (vs. optimal) cell therapy look like?
Advanced made, Patient of Type 1 Outer and Inner compartments of spheres (not capsule) no immune suppression continuous secretion of enzyme Insulin independence without immune suppression
Volume to have of-the-shelf inventory oxegenation in location lymphatic and vascularization conrol the whole process modular platform learning from others
Keep eyes open, waiting the Pandemic to end and enable working back on all the indications
Portfolio of MET, Mimi Emerging Therapies
Learning from the Pandemic – operationalize the practice science, R&D leaders, new collaboratives at NIH, FDA, Novartis
Pursue programs that will yield growth, tropic diseases with Gates Foundation, Rising Tide pods for access CGT within Novartis Partnership with UPenn in Cell Therapy
Cost to access to IP from Academia to a Biotech CRISPR accessing few translations to Clinic
Protein degradation organization constraint valuation by parties in a partnership
Novartis: nuclear protein lipid nuclear particles, tamplate for Biotech to collaborate
Game changing: 10% of the Portfolio, New frontiers human genetics in Ophthalmology, CAR-T, CRISPR, Gene Therapy Neurological and payloads of different matter
The Voice of Dr. Seidman – Her abstract is cited below
The ultimate opportunity presented by discovering the genetic basis of human disease is accurate prediction and disease prevention. To enable this achievement, genetic insights must enable the identification of at-risk
individuals prior to end-stage disease manifestations and strategies that delay or prevent clinical expression. Genetic cardiomyopathies provide a paradigm for fulfilling these opportunities. Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction with normal or enhanced systolic performance and a unique histopathology: myocyte hypertrophy, disarray and fibrosis. Dilated cardiomyopathy (DCM) exhibits enlarged ventricular volumes with depressed systolic performance and nonspecific histopathology. Both HCM and DCM are prevalent clinical conditions that increase risk for arrhythmias, sudden death, and heart failure. Today treatments for HCM and DCM focus on symptoms, but none prevent disease progression. Human molecular genetic studies demonstrated that these pathologies often result from dominant mutations in genes that encode protein components of the sarcomere, the contractile unit in striated muscles. These data combined with the emergence of molecular strategies to specifically modulate gene expression provide unparalleled opportunities to silence or correct mutant genes and to boost healthy gene expression in patients with genetic HCM and DCM. Many challenges remain, but the active and vital efforts of physicians, researchers, and patients are poised to ensure success.
Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech
One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.
What is driving the interest in rare diseases?
What are the biggest barriers to making breakthroughs ‘routine and affordable?’
What is the role of retrospective and prospective natural history studies in rare disease? When does the expected value of retrospective disease history studies justify the cost?
Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases? How does this impact the collection of natural history data?
The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell
Senior Health and Science Reporter, CNBC
CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps
SVP & Chief Business Officer, Novartis Gene Therapies
Reimagine medicine with collaboration at MGH, MDM condition in children
The Science is there, sustainable processes and systems impact is transformational
Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect
Head, Pharmaceuticals Research & Development, Bayer AG
CGT – 2016 and in 2020 new leadership and capability
Disease Biology and therapeutics
Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular
During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions
GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:
EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG
CGT will bring treatment to cure, delivery of therapies
Be a Leader repair, regenerate, cure
Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products
Bayer strategy: build platform for use by four domains
Gener augmentation
Autologeneic therapy, analytics
Gene editing
Oncology Cell therapy tumor treatment: What kind of cells – the jury is out
Of 23 product launch at Bayer no prediction is possible some high some lows
Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD
Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.
Today’s panel is made up of pioneers who represent foundational aspects of gene editing. They will discuss the movement of the technology into the therapeutic mainstream.
Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
When to use what editing tool – pros and cons of traditional gene-editing v. base editing. Is prime editing the future? Specific use cases for epigenetic editing.
When we reach widespread clinical use – role of off-target editing – is the risk real? How will we mitigate? How practical is patient-specific off-target evaluation?
There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:
What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?
Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:
How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?
Will oligonucleotides improve as a class that will make them even more effective? Are further advancements in backbone chemistry anticipated, for example.
Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
Are small molecules a threat to oligonucleotide-based therapies?
Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides? Is there a place for multiple mechanism oligonucleotide medicines?
Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021 8:30 AM – 8:55 AM
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.Christine Seidman, MD
Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech
One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.
What is driving the interest in rare diseases?
What are the biggest barriers to making breakthroughs ‘routine and affordable?’
What is the role of retrospective and prospective natural history studies in rare disease? When does the expected value of retrospective disease history studies justify the cost?
Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases? How does this impact the collection of natural history data?
The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell
Senior Health and Science Reporter, CNBC
CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps
SVP & Chief Business Officer, Novartis Gene Therapies
Reimagine medicine with collaboration at MGH, MDM condition in children
The Science is there, sustainable processes and systems impact is transformational
Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect
Head, Pharmaceuticals Research & Development, Bayer AG
CGT – 2016 and in 2020 new leadership and capability
Disease Biology and therapeutics
Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular
During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions
GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:
EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG
CGT will bring treatment to cure, delivery of therapies
Be a Leader repair, regenerate, cure
Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products
Bayer strategy: build platform for use by four domains
Gener augmentation
Autologeneic therapy, analytics
Gene editing
Oncology Cell therapy tumor treatment: What kind of cells – the jury is out
Of 23 product launch at Bayer no prediction is possible some high some lows
Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD
Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.
Today’s panel is made up of pioneers who represent foundational aspects of gene editing. They will discuss the movement of the technology into the therapeutic mainstream.
Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
When to use what editing tool – pros and cons of traditional gene-editing v. base editing. Is prime editing the future? Specific use cases for epigenetic editing.
When we reach widespread clinical use – role of off-target editing – is the risk real? How will we mitigate? How practical is patient-specific off-target evaluation?
There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:
What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?
Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:
How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?
Will oligonucleotides improve as a class that will make them even more effective? Are further advancements in backbone chemistry anticipated, for example.
Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
Are small molecules a threat to oligonucleotide-based therapies?
Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides? Is there a place for multiple mechanism oligonucleotide medicines?
Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?
Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
Partner, Mass General Brigham Innovation Fund
Strategies, success what changes are needed in the drug discovery process Speakers:
Bring disruptive frontier as a platform with reliable delivery CGT double knock out disease cure all change efficiency and scope human centric vs mice centered right scale of data converted into therapeutics acceleratetion
Innovation in drugs 60% fails in trial because of Toxicology system of the future deal with big diseases
Moderna is an example in unlocking what is inside us Microbiome and beyond discover new drugs epigenetics
Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization How to systematically scaling up systematize the discovery and the production regulatory innovations
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
Director, Neuroregeneration Research Institute, McLean
Professor, Neurology and Neuroscience, MGH, HMS
Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all Translational medicine funding stem cells enormous opportunities
Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
VP, Venture, Mass General Brigham
Saturation reached or more investment is coming in CGT
Pharmacologic agent in existing cause another disorders locomo-movement related
efficacy Autologous cell therapy transplantation approach program T cells into dopamine generating neurons greater than Allogeneic cell transplantation
Current market does not have delivery mechanism that a drug-delivery is the solution Trials would fail on DELIVERY
Immune suppressed patients during one year to avoid graft rejection Autologous approach of Parkinson patient genetically mutated reprogramed as dopamine generating neuron – unknowns are present
Circuitry restoration
Microenvironment disease ameliorate symptoms – education of patients on the treatment
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.
ALL THE TWEETS PRODUCED ON MAY 21, 2021 INCLUDE THE FOLLOWING:
Bob Carter, MD, PhD Chairman, Department of Neurosurgery, MGH William and Elizabeth Sweet, Professor of Neurosurgery, HMS Neurogeneration REVERSAL or slowing down?
Penelope Hallett, PhD NRL, McLean Assistant Professor Psychiatry, HMS efficacy Autologous cell therapy transplantation approach program T cells into dopamine genetating cells greater than Allogeneic cell transplantation
Roger Kitterman VP, Venture, Mass General Brigham Saturation reached or more investment is coming in CGT Multi OMICS and academia originated innovations are the most attractive areas
Peter Kolchinsky, PhD Founder and Managing Partner, RA Capital Management Future proof for new comers disruptors Ex Vivo gene therapy to improve funding products what tool kit belongs to
Chairman, Department of Neurosurgery, MGH, Professor of Neurosurgery, HMS Cell therapy for Parkinson to replace dopamine producing cells lost ability to produce dopamine skin cell to become autologous cells reprogramed
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH Off-th-shelf one time treatment becoming cure Intact tissue in a dish is fragile to maintain metabolism to become like semiconductors
Ole Isacson, MD, PhD Director, Neuroregeneration Research Institute, McLean Professor, Neurology and Neuroscience, MGH, HMS Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all
Erin Kimbrel, PhD Executive Director, Regenerative Medicine, Astellas In the ocular space immunogenecity regulatory communication use gene editing for immunogenecity Cas1 and Cas2 autologous cells
Nabiha Saklayen, PhD CEO and Co-Founder, Cellino scale production of autologous cells foundry using semiconductor process in building cassettes by optic physicists
Joe Burns, PhD VP, Head of Biology, Decibel Therapeutics Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation control by genomics
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH first drug required to establish the process for that innovations design of animal studies not done before
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization
David Berry, MD, PhD CEO, Valo Health GP, Flagship Pioneering Bring disruptive frontier platform reliable delivery CGT double knockout disease cure all change efficiency scope human centric vs mice centered right scale acceleration
Kush Parmar, MD, PhD Managing Partner, 5AM Ventures build it yourself, benefit for patients FIrst Look at MGB shows MEE innovation on inner ear worthy investment
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Frustration with supply chain during the Pandemic, GMC anticipation in advance CGT rapidly prototype rethink and invest proactive investor .edu and Pharma
A highly effective platforms for the ex utero culture of post-implantation mouse embryos have been developed in the present study by scientists of the Weizmann Institute of Science in Israel. The study was published in the journal Nature. They have grown more than 1,000 embryos in this way. This study enables the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms.
At Day 11 of development more than halfway through a mouse pregnancy the researchers compared them to those developing in the uteruses of living mice and were found to be identical. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. The mouse embryos looked perfectly normal. All their organs developed as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute. But, the lab-grown embryos becomes too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient. So, a suitable mechanism for blood supply is required to be developed.
Till date the only way to study the development of tissues and organs is to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like in snapshots than in live videos. This research will help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. This will allow researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals. In the future it may be possible to develop a human embryo from fertilization to birth entirely outside the uterus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.
Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require deeper understanding of the healthy heart’s molecular processes. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavor. Here, using state-of-the-art analyses of large-scale single-cell and nuclei transcriptomes, we characterise six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes, and fibroblasts, revealing distinct atrial and ventricular subsets with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment we identify cardiac resident macrophages with inflammatory and protective transcriptional signatures. Further, inference of cell-cell interactions highlight different macrophage-fibroblast-cardiomyocyte networks between atria and ventricles that are distinct from skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a healthy reference for future studies.
Author information
Author notes
These authors contributed equally: Monika Litviňuková, Carlos Talavera-López, Henrike Maatz, Daniel Reichart
These authors jointly supervised this work: J. G. Seidman, Christine E. Seidman, Michela Noseda, Norbert Hubner, Sarah A. Teichmann
Affiliations
Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
Monika Litviňuková, Carlos Talavera-López, Krzysztof Polanski, Kenny Roberts, Liz Tuck, Eirini S. Fasouli, Hongbo Zhang, Omer Bayraktar & Sarah A. Teichmann
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Monika Litviňuková, Henrike Maatz, Catherine L. Worth, Eric L. Lindberg, Masatoshi Kanda, Giannino Patone & Norbert Hubner
Department of Genetics, Harvard Medical School, Boston, MA, United States
Daniel Reichart, Emily R. Nadelmann, Daniel M. DeLaughter, Hiroko Wakimoto, Joshua M. Gorham, J. G. Seidman & Christine E. Seidman
Dept Physics/Cavendish Laboratory, University of Cambridge, JJ Thompson Ave, Cambridge, CB3 0EH, United Kingdom
Sarah A. Teichmann
Department of Cardiology, University Heart & Vascular Center, University of Hamburg, Hamburg, Germany
Daniel Reichart
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Michael Lee, Sara Samari, Joseph J. Boyle & Michela Noseda
British Heart Foundation Centre of Research Excellence and Centre of Regenerative Medicine, Imperial College London, London, United Kingdom
Michela Noseda
Department of Surgery, University of Cambridge, NIHR Cambridge Biomedical Centre, and Cambridge Biorepository for Translational Medicine, Cambridge, United Kingdom
Krishnaa T. Mahbubani & Kourosh Saeb-Parsy
Charité-Universitätsmedizin, Berlin, Germany
Norbert Hubner
Berlin Institute of Health (BIH), Berlin, Germany
Norbert Hubner
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
Barbara McDonough & Norbert Hubner
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, United States
Barbara McDonough & Christine E. Seidman
Howard Hughes Medical Institute, Chevy Chase, MD, United States
Christine E. Seidman
Institute of Computational Biology (ICB), HMGU, Neuherberg, Germany
Matthias Heinig
Department of Informatics, Technische Universitaet Muenchen (TUM), Munich, Germany
Matthias Heinig
Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Hao Zhang, Anissa Viveiros & Gavin Y. Oudit
Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Hao Zhang, Anissa Viveiros & Gavin Y. Oudit
Department of Histology and Embryology of Zhongshan School of Medicine, Sun-Yat Sen University, Guangzhou, China
Hongbo Zhang
Department of Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
Studies have shown that regular physical activity can contribute to longer life and less risk for serious health problems, such as heart disease, type 2 diabetes, obesity and some cancers. The Centers for Disease Control (CDC) continues to partner with national groups, states and communities to provide quality education around the physical activity.
An analysis, Adult Physical Inactivity Prevalence Maps by Race/Ethnicity, published on the CDC web site in January 2020 demonstrated that “all states and territories had more than 15 percent of adults who were physically inactive.” The analysis included state maps that used combined data from 2015 through 2018 with “noticeable differences in the prevalence of physical inactivity by race/ethnicity.” Physical inactivity is reported as “no leisure-time physical activity.”
Here are findings from their analysis:
The South (28.0%) had the highest prevalence of physical inactivity, followed by the Northeast (25.6%), Midwest (25.0%), and the West (20.5%).
In 7 states (Tennessee, Oklahoma, Louisiana, Alabama, Kentucky, Arkansas, and Mississippi), and 2 US territories (Puerto Rico, and Guam), 30% or more of adults were physically inactive.
In 4 states (Colorado, Washington, Utah, and Oregon) and the District of Columbia, 15% to less than 20% of adults were physically inactive.
In 24 states, 20% to less than 25% of adults were physically inactive.
In 15 states, 25% to less than 30% of adults were physically inactive.
More analysis showed:
Hispanics (31.7%) had the highest prevalence of physical inactivity, followed by non-Hispanic blacks (30.3%) and non-Hispanic whites (23.4%).
In the majority of states, non-Hispanic blacks and Hispanics had a significantly higher prevalence of inactivity than non-Hispanic whites.
5 states and Puerto Rico had a physical inactivity prevalence of 30% or higher among non-Hispanic white adults.
22 states and Puerto Rico had a physical inactivity prevalence of 30% or higher among Hispanic adults.
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