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Posts Tagged ‘Induced pluripotent stem cell’


Previously unseen immune reaction identified for stem cell transplants.

Reporter: Stephen J. Williams, Ph.D.

Reposted from at http://health-innovations.org/2014/11/21/previously-unseen-immune-reaction-identified-in-stem-cell-transplants/

 

Mouse cells and tissues created through nuclear transfer can be rejected by the body because of a previously unknown immune response to the cell’s mitochondria, according to an international study in mice by researchers at the Stanford University, MIT and colleagues in Germany and England.  The findings reveal a likely, but surmountable, hurdle if such therapies are ever used in humans, the researchers said.  The opensource study is published in Cell Stem Cell.

Stem cell therapies hold vast potential for repairing organs and treating disease. The greatest hope rests on the potential of pluripotent stem cells, which can become nearly any kind of cell in the body. One method of creating pluripotent stem cells is called somatic cell nuclear transfer, and involves taking the nucleus of an adult cell and injecting it into an egg cell from which the nucleus has been removed.

The promise of the SCNT method is that the nucleus of a patient’s skin cell, for example, could be used to create pluripotent cells that might be able to repair a part of that patient’s body.  One attraction of SCNT has always been that the genetic identity of the new pluripotent cell would be the same as the patient’s, since the transplanted nucleus carries the patient’s DNA.

The hope has been that this would eliminate the problem of the patient’s immune system attacking the pluripotent cells as foreign tissue, which is a problem with most organs and tissues when they are transplanted from one patient to another.

Stanford University have raised the possibility in the past that the immune system of a patient who received SCNT-derived cells might still react against the cells’ mitochondria, which act as the energy factories for the cell and have their own DNA. This reaction could occur because cells created through SCNT contain mitochondria from the egg donor and not from the patient, and therefore could still look like foreign tissue to the recipient’s immune system.

That hypothesis was never tested until the team took up the challenge.  There was a thought that because the mitochondria were on the inside of the cell, they would not be exposed to the host’s immune system.  The current study found that this was not the case.

The team used cells that were created by transferring the nuclei of adult mouse cells into enucleated eggs cells from genetically different mice. When transplanted back into the nucleus donor strain, the cells were rejected although there were only two single nucleotide substitutions in the mitochondrial DNA of these SCNT-derived cells compared to that of the nucleus donor.  The team were surprised to find that just two small differences in the mitochondrial DNA was enough to cause an immune reaction.

Until recently, researchers were able to perform SCNT in many species, but not in humans. When scientists at the Oregon Health and Science University announced success in performing SCNT with human cells last year, it reignited interest in eventually using the technique for human therapies. Although many stem cell researchers are focused on a different method of creating pluripotent stem cells, called induced pluripotent stem cells, there may be some applications for which SCNT-derived pluripotent cells are better suited.

The immunological reactions reported in the new paper will be a consideration if clinicians ever use SCNT-derived stem cells in human therapy, but such reactions should not prevent their use.   This research informs the medical community of the margin of safety that would be required if, in the distant future, researchers need to use SCNT to create pluripotent cells to treat someone.  In that case, clinicians would likely be able to handle the immunological reaction using the immunosuppression methods that are currently available.

In the future, scientists might also lessen the immune reaction by using eggs from someone who is genetically similar to the recipient, such as a mother or sister.

Source:  Stanford University School of Medicine

The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies.  SCNT-Derived ESCs with Mismatched Mitochondria Trigger an Immune Response in Allogeneic Hosts.  Schrepfer et al 2014.

The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies. SCNT-Derived ESCs with Mismatched Mitochondria Trigger an Immune Response in Allogeneic Hosts. Schrepfer et al 2014.

SCNT (somatic cell nuclear transfer)

scnt

Possible ways to generate immune-compatible derivatives of pluripotent cells. From Nature Reviews

From the following article: Derive and conquer: sourcing and differentiating stem cells for therapeutic applications

In genetics and developmental biology, somatic cell nuclear transfer (SCNT) is a laboratory technique for creating an ovum with a donor nucleus. It can be used in embryonic stem cell research, or in regenerative medicine where it is sometimes referred to as “therapeutic cloning.”

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Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP

Introduction
This is the second part of a series on toxicities of therapeutic medications, the first being on the impact on drug development of early phase failure to identify toxicities that are found in late stage trials and result in withdrawal.  This portion will go into details of identifying the effects clinically and give some examples.  In the future, the design of therapies, the identification of high probability successful genomic targets, and more accurate patient selection will transform the approach to development, clinical trials, and clinical use of pharmaceuticals in patients.

Cardiotoxicity and Cardiomyopathy

refer to: What are cardiotoxicity and cardiomyopathy?

The Scott Hamilton Cares Initiative
Cardiotoxicity is a condition of heart muscle functional impairment from toxicity as an
  • adverse secondary effect of taking an essential medication, or
  • as a result of interactions between prescribed medications that result in heart damage,
  • usually dose and time related.
If severe, the adverse effect of chemotherapy may lead to cardiomyopathy.  While cardiomyopathy might be a result of treatments, such as chemotherapeutic medications, it may also caused by a group of diseases or disorders, leading to
  • damaged myocardiocytes, and the injury leads to
  • insufficient cardiac output, referred to as
  • heart failure.
Cardiomyopathy has many causes, singly or in combination:
  • viruses – such as,
    • coxsackie B,
    • human immunodeficiency virus (HIV)
  • systemic inflammatory disorder
    • systemic lupus erythematosis
  • Amyloidosis – amyloid protein deposits in the myocardium alone, and/or other organs
  • Infection –
    • bacterial (tetanus),
    • parasitic (Chaga’s disease)
    • Rheumatic fever
  •  high blood pressure
  • Chronic or long-term alcohol use (B vitamin deficiency)
  • Endocrine disease, such as hyperthyroidism
  • Thiamine and Vitamin B deficiency
  • Radiation therapy
  • Medications – anthracyclines.

Anthracyclines may be used to treat leukemia, lymphoma, multiple myeloma, breast cancer, and sarcoma. A commonly used anthracycline is called doxorubicin (Adriamycin®).

  • cardiomyopathy may also result from genetic defects
  • illegal drugs and toxic substances, cocaine, may also produce serious myocardial damage

With certain drugs, such as doxorubicin, there is a dose at which these cardiotoxic effects on the heart may occur.
An echocardiogram, or a radionuclide ventriculography scan, is performed

  • prior to initiating a cardiotoxic medication
  • to determine baseline cardiac function., and
  • repeated at intervals to monitor heart function while receiving cardiotoxic medications.

The ejection fraction (EF) is a percentage of blood pumped out into the body during each heartbeat. An EF of 50%-75% is considered normal.

  • The lower the ejection fraction, the more severe the heart failure may be.
This may determine if the cardiotoxic drug has caused cardiomyopathy.

Symptoms of cardiomyopathy:

  • fatigue
  •  shortness of breath
  •  fever and aching of the joints,
      • all characteristic of a flu-like illness.
  • Or, sudden heart failure or sudden cardiac death without any prior symptoms.
    • swollen feet and ankles
    • distended neck veins
    • tachycardia
    • dyspnea while reclining

Diagnosis:

  • history & physical examination
  • laboratory tests
  • EKG
  • Chest x-ray
  • Echocardiography
  • Cardiac cath
  • Angiography

Treatment:

  • Dexraoxane HCL –  doxorubicin
  • ACE inhibitors
  • Beta-blockers
  • Diuretics
  • Digoxin

 Biomolecular Screening for Drug Toxicity

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells

O Sirenko, C Crittenden, N Callamaras, J Hesley, Yen-Wen Chen, et al.
 A sufficient percentage of drugs fail in clinical studies due to cardiac toxicity that the development of new, sensitive in vitro assays that can evaluate potential adverse effects on cardiomyocytes is needed. Cell-based models are more clinically relevant than those used in practice. Human-induced pluripotent stem cell–derived cardiomyocytes are especially attractive because
  • they express ion channels and
  • demonstrate spontaneous mechanical and electrical activity
    • similar to adult cardiomyocytes.
This study introduces techniques for measuring the impact of pharmacologic compounds on the beating rate of cardiomyocytes with ImageXpress Micro and FLIPR Tetra systems. The assays employ
calcium-sensitive dyes to monitor changes in Ca2+ fluxes
  • synchronous with cell beating,
This method allows monitoring of the
  • beat rate
  • amplitude, and
  • other parameters.
The system detects
  • concentration-dependent atypical patterns caused by
  • hERG inhibitors and other ion channel blockers.
In addition,
  • both positive and negative chronotropic effects on cardiac rate can be observed and
  • IC50 values determined.
This methodology is well suited for safety testing and can be used to estimate efficacy and dosing of drug candidates prior to clinical studies.
J Biomol Screen Jan 2013;18(1): 39-53  http://dx.doi.org/10.1177/1087057112457590

Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.

L Guo, RMC Abrams, JE Babiarz, JD Cohen, S Kameoka, et al.
 Early prediction of drug-induced toxicity is needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition.
  • Cardiotoxicity accounts for about one third of safety-based withdrawn pharmaceuticals.
This study reports a high-throughput functional assay,  detailing a model that accurately detects
  • drug-induced cardiac abnormalities.
It employs
  • induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
  • Using 96-well plates with interdigitated electrode arrays  detect
    • assess impedance,
    • the rhythmic, synchronous contractions of the iPSC-CMs
Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in
  • compound-specific changes in the beat rate and/or
  • the amplitude of the impedance measurement.
Changes in impedance for the compounds tested were comparable with the results from a related technology,
  • electric field potential assessment obtained from microelectrode arrays.
Using the results from the set of compounds,
  • an index of drug-induced arrhythmias was calculated,
  • which enabled the determination of a drug’s proarrhythmic potential.
This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology.
Toxicol Sci. Sep 2011; 123 (1):281-9  21693436

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling.

JE Babiarz, M Ravon, S Sridhar, P Ravindran, B Swanson,  et al.
This study is a detailed comparison of the mRNA and miRNA transcriptomes
  • across differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and
  • biopsies from fetal, adult, and hypertensive human hearts
Gene ontology analysis of the mRNA expression levels of the hiPSCs differentiating into cardiomyocytes
revealed 3 distinct groups of genes:
  • pluripotent specific,
  • transitional cardiac specification, and
  • mature cardiomyocyte specific.
Hierarchical clustering of the mRNA data revealed that the transcriptome of hiPSC cardiomyocytes
  • stabilizes 20 days after initiation of differentiation.
But analysis of cells continuously cultured for 120 days indicated that
  • the cardiomyocytes continued to mature toward a more adult-like gene expression pattern.
Analysis of cardiomyocyte-specific miRNAs (miR-1, miR-133a/b, and miR-208a/b) revealed
  • an miRNA pattern indicative of stem cell to cardiomyocyte specification.
A biostatistitical approach integrated the miRNA and mRNA expression profiles revealing a
  • cardiomyocyte differentiation miRNA network and
  • identified putative mRNAs targeted by multiple miRNAs.
Together, these data reveal the
miRNA network in human heart development and
  • support the notion that overlapping miRNA networks
  • re-enforce transcriptional control during developmental specification.
Stem Cells Dev. 2012 Jul 20;21 (11):1956-65  22050602

Comparative Gene Expression Profiling in Human Induced Pluripotent Stem Cell Derived Cardiocytes and Human and Cynomolgus Heart Tissue.

D Puppala, LP Collis, SZ Sun, V Bonato, X Chen, B Anson, et al.  Compound Safety Prediction.
Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity.  The authors describe
  • the gene expression profile of human induced pluripotent stem cell derived cardiocytes (iCC)
  • post-thaw over a period of 42 days in culture and
  • compare this profile to human fetal and adult as well as
  • adult cynomolgus nonhuman primate (NHP: Macaca fascicularis) heart tissue.
The results indicate that iCC express relevant cardiac markers such as
  • ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1 and KCNH2),
  • tissue specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2 and TNNI3),
  • transcription factors (NKX2.5, GATA4 and GATA6), and
  • lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42).

A functional evaluation of contractility of the iCC showed

  • functional and pharmacological correlations with myocytes isolated from adult NHP hearts.
The results suggest that stem cell derived cardiocytes may represent
  • a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation.
Toxicol Sci. Sep 14 2012;:   22982684

Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes:
Bioenergetics and Utilization in Safety Screening.

P Rana, B Anson, S Engle, Y Will.   Compound Safety Prediction. Pfizer Global R&D, Groton CT.
Cardiotoxicity remains the number one reason for drug withdrawal from the market and FDA issued black box warnings; thus
  • demonstrating the need for more predictive preclinical safety screening,
  • especially early in the drug discovery process.
Whereas hERG screening has become routine to mitigate proarrhythmic risk,
  • the development of in vitro assays predicting additional on- and off-target biochemical toxicities
  • will benefit from cellular models exhibiting true cardiomyocyte characteristics
    • such as, native tissue-like mitochondrial activity.
An hypothesis was tested  for using human stem cell derived tissue cells by using a combination of
  • flux analysis,
  • gene and protein expression, and
  • toxicity-profiling techniques
    • to characterize mitochondrial function
    • in induced pluripotent stem cell (iPSC)-derived human cardiomyocytes
      • in the presence of differing carbon sources
      • over extended periods in cell culture.
Functional analyses demonstrate that iPSC-derived cardiomyocytes:
1) are capable of utilizing anaerobic or aerobic respiration depending upon the available carbon substrate,
2) are bioenergetically closest to adult heart tissue cells when cultured in galactose or galactose supplemented with fatty acids, and
3) show a dose dependent toxicity profile to a variety of kinase inhibitors with known clinical cardiac liabilities.
Furthermore, gene and protein expression analyses revealed that in comparison to adult cardiac tissue,
  • iPSCs-derived cardiomyocytes possess a qualitatively similar expression pattern of mitochondrial genes,
  • an up-regulation of apoptotic and antioxidant genes, and
  • a mitochondrial transcription pattern that is similar across different carbon substrates
  • despite showing changes in protein levels and functional bioenergetic adaptation.
Toxicol Sci. 2012 Jul 27;:   22843568

Decreasing cardiac chamber sizes and associated heart dysfunction in COPD – role of hyperinflation.

H Watz, B Waschki, T Meyer, G Kretschmar, A Kirsten, M Claussen, H Magnussen
This study examined the relationship of
  • lung function with heart size and heart dysfunction and
  • associated consequences for 6-minute walk distance (6MWD)
    • in patients with COPD of different severity.
METHODS:   138 patients with COPD (GOLD I-IV)
  • the size of all cardiac chambers,
  • left ventricular diastolic dysfunction (relaxation and filling), and
  • global right ventricular dysfunction (Tei-index)
    • were measured by echocardiography .
  • lung function (spirometry, bodyplethysmography, diffusion capacity) and
  • 6MWD …. were measured.
RESULTS: Size of all cardiac chambers decreased with GOLD stages. Overall,
moderate relationships existed between
  • variables of lung function and cardiac chamber sizes.
  • Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC],
  • functional residual capacity, and residual volume)
showed stronger associations with
  • cardiac chamber sizes than
  • airway obstruction or diffusion capacity.
IC/TLC ratio correlated best with cardiac chamber sizes and was
  • an independent predictor of cardiac chamber sizes
    • after adjustment for body surface area.
Patients with an IC/TLC ratio <!–= 0.25 had a significantly–>
  • impaired left ventricular diastolic filling pattern and
  • a significantly impaired Tei-index
    • compared to patients with an IC/TLC ratio > 0.25.
An impaired left ventricular diastolic filling pattern was independently associated with
  • a reduced 6MWD.
An increasing severity of COPD is associated with a decreasing heart size.
Hyperinflation in patients with COPD might have an important role with respect to
  • heart size and
  • cardiac dysfunction
Chest. Feb 26 2010;:   20190002  Cit:4

Cardiovascular Events After Clarithromycin Use in Lower Respiratory Tract Infections
Analysis of Two Prospective Cohort Studies

S Schembri, PA Williamson, PM Short, A Singanayagam, A Akram, et al. British Medical Journal
Acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia are common causes of admission to a hospital.
Antibiotics, including clarithromycin, are commonly prescribed during acute exacerbations of chronic obstructive pulmonary disease, especially
  • in the presence of increased breathlessness,
  • sputum volume, and
  • purulence.
 Use of macrolide antibiotics in community acquired pneumonia has been consistently associated with improved short term mortality in observational studies,
and national and international guidelines therefore recommend their use in combination with β lactams for patients admitted to hospital.

Widespread use of macrolide antibiotics has been accompanied by concerns about adverse effects on cardiovascular morbidity and mortality.
A retrospective study of erythromycin use in 1,249,943 patients identified an increase in deaths from cardiovascular disease.
Azithromycin was shown to have a similar association with increased cardiovascular deaths

  • during the time of administration.

CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients with Ischemic Heart Disease trial) was a double blind, placebo controlled trial
showing that a two week course of clarithromycin administered to patients with coronary heart disease 

  • increased cardiovascular and all cause mortality
The increased mortality rate (clear of pulmonary infection)
  • persisted for three years after discontinuation of the drug.

A recent meta-analysis of 17 trials of antibiotics in coronary heart disease showed

  • increased long term mortality after macrolides, primarily due
  • to increased deaths from cardiovascular disease.

However, no studies have examined the long term effect of clarithromycin on cardiovascular events and mortality in patients

  • after acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia.

Therefore, this prospective cohort study was undertaken to examine the association of clarithromycin with cardiovascular events

  • in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Population.

  • 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease
  • and 1631 patients admitted with community acquired pneumonia.

Main Outcome Measures.

Hazard ratios for cardiovascular events at one year (defined as hospital admissions with

  • acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and
  • admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina).

Secondary outcomes were all cause and cardiovascular mortality at one year.

Results.

  •  268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and
  • 171 in the community acquired pneumonia cohort over one year.

After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease

  • was associated with an increased risk of cardiovascular events and acute coronary syndrome—
  • hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68).
After multivariable adjustment, clarithromycin use in community acquired pneumonia
  •  was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38)
  • but not acute coronary syndrome (1.65, 0.97 to 2.80).
This association was found between clarithromycin use in acute exacerbations of COPD and
  • cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26)
  • but not all cause mortality (1.16, 0.90 to 1.51) .

No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality.
Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with

  • acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

 Timing of Cardiovascular Events

The study found no significantly increased risk of cardiovascular events while patients were taking clarithromycin in the COPD cohort
(hazard ratio 1.73, 0.71 to 4.25), but
  • an increased risk was present after the clarithromycin course ended (1.41, 1.05 to 1.89).
In the community acquired pneumonia cohort, the hazard ratio for association between clarithromycin use and cardiovascular events
was 1.84 (0.75 to 4.51) during clarithromycin use and 1.66 (1.14 to 2.43) after the antibiotic was stopped.

Association With Duration of Antibiotic Use

Longer courses of clarithromycin were associated with more cardiovascular events. The median duration of treatment was seven days in both cohorts.
Less than three days of clarithromycin treatment was not associated with cardiovascular events in the chronic obstructive pulmonary disease cohort
(hazard ratio 0.89, 0.50 to 1.57) or the community acquired pneumonia cohort (0.63, 0.15-2.65), compared with patients who did not receive clarithromycin.

Effect of Age and Cardiovascular Risk Status

The hazard ratios of the effect of clarithromycin on cardiovascular events in such patients were
  • 1.35 (0.94 to 1.95) in those with a high cardiovascular risk and 0.88 (0.20 to 3.96) in those with a low risk.

The lowest hazard ratios for cardiovascular events were in patients aged 60 or below (1.01, 0.36 to 2.91).
The hazard ratio was 1.47 (1.01 to 2.14) for patients aged 60-79, and a higher risk was associated with

  • clarithromycin use in patients aged over 80 (hazard ratio 1.68, 1.05 to 2.69).

Use of Other Antibiotics

Use of β lactam or doxycycline was not associated with increased cardiovascular events
  • (hazard ratios 1.06 (0.83 to 1.37) and 0.96 (0.61 to 1.51), respectively)
in the chronic obstructive pulmonary disease cohort compared with patients not receiving antibiotics.

Possible Explanations for Findings

There was a strong association between prolonged (more than seven days) courses of clarithromycin and
  • cardiovascular events,
    • which strengthens the case for a true biological cause.

The association between duration of antibiotic treatment and cardiovascular events

  • could also represent residual confounding by severity of illness.

How do the results point to the effect on outcome after cessation of the drug?  The authors support an ischaemic mechanism.
Clarithromycin may activate macrophages, leading to an inflammatory cascade resulting in more vulnerable plaques that

  • over time may lead to acute coronary syndromes or sudden cardiac death by plaque rupture.

 Conclusion

Prolonged courses of clarithromycin (more than seven days) may be associated with

  • increased risk of cardiovascular events,
  • especially in patients with a pre-existing history of coronary heart disease.

This may be of particular importance given recent data supporting long term macrolide use

  • to prevent exacerbations of chronic obstructive pulmonary disease.

Biomarkers Role in Drug Development

Biomarkers: An indispensible addition to the drug development toolkit

Biomarkers are becoming an essential part of clinical development. In this white paper, Thomson Reuters explores
the role of biomarkers as evaluative tools in improving clinical research and the challenges this presents.
The potential of biomarkers to

  • improve decision making,
  • accelerate drug development and
  • reduce development costs

is discussed with insights into a faster alternative to the conventional drug development approach and the promise of

  • safer drugs,
  • in greater numbers,
  • approved more quickly.
The attrition rate for drugs in clinical development is high: the percentage of tested products
  • entering phase I trials that eventually gain regulatory approval has been estimated at a paltry 8%.
Many of these failures happen late in clinical trials, with the consequence that expenditure in clinical drug development is increasing.
One study calculated that the cost of developing a drug increased by over 50% between 2002 and 2007. The related concern is that
very few drugs are making it out of the clinical research pipeline.
In 2007, the FDA approved just 17 new molecular entities and 2 biologic licenses, the lowest number since 1983.
The problem is mainly due to a gap in the industry’s ability to predict a drug candidate’s performance early, and with a large degree of certainty.
The convention in clinical research has been to measure the performance of novel therapies using clinical outcomes. This approach is
laborious, inexact and, as the US Food and Drug Administration (FDA ) puts it, decades old.

Why and what kinds of biomarkers do we determine are ESSENTIAL?

Biomarkers — a measure of
  • a normal biological process in the body,
  • a pathological process, or
  • the response of the body to a therapy —
may offer information about
  • the mechanism of action of the drug,
  • its efficacy, its safety and
  • its metabolic profile.
They feature heavily in the FDA ’s Critical Path Opportunities List for their potential
  • to speed the development and approval of medical products.
  • Moreover, they can predict drug efficacy more quickly than conventional clinical endpoints.
The first three examples are measures of drug efficacy and treatment response, but are not indicators of TOXICITY.

In 1960, researchers discovered that some patients with chronic myelogenous leukemia (CML), a form of adult leukemia

  • in which there is a proliferation of myeloid cells in the bone marrow,
  • have a specific genetic change associated with their cancer, a shortened version of chromosome.

The Philadelphia chromosome is caused by a translocation between chromosomes 9 and 22. The consequence of this genetic swap

  • is the creation of the BCR-ABL ‘oncogene’;
  • this cancer-causing gene produces a protein with elevated tyrosine kinase activity
  • that induces the onset of leukemia.

Researchers were able to use the Philadelphia chromosome as a biomarker

  • to indicate which patients would benefit from drug candidates (tyrosine-kinase inhibitors)
    • specifically targeting the rogue protein.

The drug imatinib (Gleevec) is a Tyr kinase inhibitor and

  • decreases the proliferation of Philadelphia chromosome+ cells,
  • slowing the progression of the disease.

Specific mutations in the BCR–ABL gene were biomarkers that predicted resistance to imatinib,

  • leading to the development of newer tyrosine-kinase inhibitors dasatinib and nilotinib.

In the late 1980’s, scientists discovered that HIV viral load could be used as a marker of disease progression
Viral load was used to show that patients receiving combination therapy had

  • a higher reduction in viral load than those on monotherapy.

Eventually, the viral load biomarker was used in the development and assessment of Highly Active Antiretroviral Therapy (HAART)
treatment regimens taken by many people living with HIV today.

The HER-2 gene and receptor was also discovered in the mid 1980’s. Between 20–30% of breast cancer patients show an

  • over-expression of the HER-2 receptor on their cancer cells (usually postmenopausal).

This biomarker indicates a higher risk of adverse outcomes, but it gave clinicians a new target for novel therapies, and

  • the antibody trastuzumab (Herceptin) was developed
  • to target HER-2 receptors in these ‘overexpressing’ patients.

 Preventing Drug Development Disasters

The need for biomarkers to guide clinical research is perhaps best highlighted in the stories of recent drug development failures.
Between 1995 and 2005, at least 34 drugs were withdrawn from the market, mainly as a result of hepatotoxic or cardiotoxic effects.

Many of us are familiar with the withdrawal in 2004 of the anti-inflammatory drug rofecoxib (Vioxx) due to concerns about its

  • increased risk of heart attack and stroke, and more recently with
  • the extremely serious adverse effects in the phase I clinical trial and subsequent failure of the monoclonal antibody, TGN1412.

TG N1412, a ‘superagonist’, produced by the firm TeGenero, stimulates an immune response. While originally intended to treat B cell
chronic lymphocytic leukemia and rheumatoid arthritis, it had been tested pre-clinically with no toxic or pro-inflammatory effects.
In 2006, six healthy male volunteers took part in a phase I clinical trial to test the safety of the candidate. Within 90 minutes of receiving the drug,

  • all six men were experiencing the beginnings of a ‘cytokine storm’, a term that describes
  • a cascade of proinflammatory cytokine release
  • leading to organ failure due to hypotension.

Although all the men survived, they required weeks of hospitalization. The cost of a failure, such as TGN1412,

  • in terms of patient health and lost resources is huge.

The TGN1412 trial failure highlighted a need for improved preclinical safety testing. It has been suggested that had procedures using safety biomarkers to

  • guide dosing and predict the toxicity of this drug been used, the disaster may not have occurred.

Biomarkers today

Today you “would not even conceive” of developing a new drug without simultaneously looking for biomarkers for
  • efficacy,
  • safety, and
  • to measure the pharmacodynamics of the drug,
says Dr Jeffrey Ross, Head of Pathology at the Albany Medical Center in New York, involved in the original work on HER-2.
The field of oncology is leading the way in the use of biomarkers in drug development. “Clinical trials are designed upon biomarker assays,”
“abstracts of phase II and III cancer trials talk about what biomarkers were selected.
  • In vivo biomarkers,
  • imaging biomarkers,
  • blood and tissue based biomarkers,

One example of a biomarker in use in oncology is circulating tumor cells (CTCs), a biomarker present in the blood of cancer patients.
At the moment, CTCs are used in the development of anti-cancer drugs as

  • an objective and direct measurement of the response of the cancer to a novel agent.

The way that clinical trials had been done previously was to enroll all patients

  • with a given disease independent of gene or phenotypic makers.
  • By selecting a population with the particular gene which is predicted
  • to be important for response to a novel therapeutic, then
    • a smaller clinical trial should be sufficient to see whether it works or not.

The chemotherapy drug irinotecan (Camptosar) is an example of personalized medicine,

  • using a biomarker to guide both clinical practice and subsequent clinical trials.

Irinotecan is used to treat advanced colorectal cancer. Once administered, irinotecan is

  • activated to the metabolite SN-38, and then
  • eventually inactivated in the body by the UGT1A1 enzyme.

In 2005, the US Food and Drug Administration added a warning to the label of the drug, stating that patients

  • homozygous for a particular a version of the UGT1A1 gene — the UGT1A1*28 allele,
  • associated with decreased UGT1A1 enzyme activity —
    • should be given a reduced dose.
Because patients with this allele clear the drug less quickly from their body than the rest of the population,
  • they effectively receive a greater exposure to the drug from the same dose.
As a consequence, they are at higher risk of potentially life-threatening side effects such as neutropenia (a decrease in white blood cells) and diarrhea.
The toxicity of irinotecan has long been a concern, and this biomarker now allows clinicians to better identify those patients who are at high risk of
  • serious side-effects (about 10% of the population are homozygous for UGT1A1*28).
And while this pharmacogenomics information has helped improve the clinical use and efficacy of irinotecan, it has also fed back into
the development of other drugs; this new understanding prompted the use of the UGT1A1 biomarker to guide other studies,
including several new irinotecan and oxaliplatin-based chemotherapy regimens.

Using preclinical biomarkers as evidence of efficacy

  • biomarkers can accelerate research by substituting for clinical symptoms as a measure of efficacy.
  • biomarkers can also replace clinical symptoms when it comes to measuring drug safety
  • an efficacy biomarker plus a safety biomarker will define not just whether a drug will work, but also what kind of dose might be relevant in humans

 Improving efficacy in cardiology

Consider the role of inflammatory marker C-reactive-protein (CRP) in cardiovascular disease. CRP is released by inflamed atherosclerotic plaques in the arteries
of individuals with coronary heart disease, and increased levels of CRP are associated with a greater risk of plaque rupture, but also of a silent heart attack.
CRP is being used as a biomarker to measure drug efficacy, in particular whether rosuvastatin (Crestor)

  • reduces the risk of cardiovascular morbidity and mortality
  • in apparently healthy individuals with low LDL-cholesterol levels but elevated CRP.

The JUPITER study (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) was halted in March 2008

  • due to firm evidence that the drug is indeed more beneficial than placebo and
  • improves the prognosis of individuals with high CRP levels.
A related biomarker of cardiovascular risk called neopterin. Just as CRP is produced by inflamed atherosclerotic plaques at risk of rupture,
neopterin is produced by activated macrophages in this inflammatory process. Circulating neopterin levels are higher in patients with ACS and may be
a marker of coronary disease activity. In addition, “Neopterin could also potentially be a marker of drug efficacy because
if you reduce the number of active macrophages in the plaque or the circulation, the levels of neopterin also decrease,” says Dr Juan Carlos Kaski,
Professor of Cardiovascular Science and Director of the Cardiovascular Biology Research Centre at St George’s University of London.

Other uses of biomarkers

These types of biomarkers can be used to drive critical ‘go/no go’ decision in drug development
Mechanistic or ‘target’ biomarkers can be used in pre-clinical or phase I trials to measure the pharmacological effect of the drug, i.e.
  • whether the drug interacts with its receptor, enzyme, or protein target,
  • whether it is distributed to the site where it needs to act,whether there is some
    • form of downstream pharmacology, and
  • the dose ranges in which the drug is pharmacologically active.
Drugs such as 5-HT4 receptor agonists (e.g. cisapride, mosapride), used in gastro-esophageal reflux disease (GERD), stimulate
  • the secretion of aldosterone as a side-effect.
Although aldosterone is not linked to GERD (and can’t be used as a biomarker of the disease), the hormone can be used
  • as a mechanistic biomarker in drug development to assess whether
    • novel 5-HT4 agonists in development have a pharmacological effect.

Discovering new biomarkers

The fundamental issue we have to deal with, both with target selection and developing better biomarkers,
  • is a better understanding of pathophysiology.
The clinical need is huge, not least in diseases like chronic obstructive pulmonary disease (COPD), an illness about which we know very little.

“COPD has very few markers to indicate severity and disease progression,” says Dr Trevor Hansel, Medical Director of the National Heart &
Lung Institute Clinical Studies Unit in London. Many pharmaceutical companies have begun to invest in ‘omics’ —

  • genomics,
  • proteomics,
  • metabonomics —

to begin to sort through this mountain of molecules and characterize biomarkers based on a molecular understanding of disease.

The ‘omics’ approach enables
  • the detection of small changes in tissue composition through protein profiling technologies such as
  • mass spectrometry and gel electrophoresis.

Essentially, it is about capturing a molecular profile from a clinical sample and converting this into

  • information about a clinical condition — for example the stage of disease or
  • what players are involved in the disease pathways.
“We will be able to look at diseases and catagorize them based on
  • biochemical or physiological findings, rather than just on symptoms” …  David Roblin, Pfizer

Companion Diagnostics and the Drug–Diagnostic Codevelopment Model

 Jan Trøst Jørgensen   Drug Development Research Nov 2012; 73(7):390-397.   http://dx.doi.org/10.1002/ddr.21029

The concept of using a predictive or selective diagnostic assay in relation to drug development goes back to the 1970s when

  • the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer.
Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen.
It is only within the last decade that this model has gained widespread acceptance. The drug and the diagnostic are interdependent, and
if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug.
This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs.
For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important
aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues, such as,
  • the biomarker selection process,
  • determination of the cut-off value, and
  • the analytical validation.

 Detecting Potential Toxicity in Mitochondria

 Brad Larson, Principal Scientist; Peter Banks, Scientific Director; BioTek Instruments, Winooski, Vt.
Mitochondrial dysfunction may be
  • inherited,
  • arise spontaneously, or
  • develop as a result of drug toxicity.
Mitochondrial toxicity as a result of pharmaceutical use may damage key organs, such as the liver and heart. For example,
  • nefazodone—a depression treatment—was withdrawn from the U.S. market after it was shown to
significantly inhibit mitochondrial respiration in liver cells, leading to liver failure. Troglitazone, an anti-diabetic and anti-inflammatory,
was withdrawn from all markets after research concluded that it caused acute mitochondrial membrane depolarization, also leading to liver failure.
Drug recalls are costly to a manufacturer’s bottom line and reputation, and more importantly, can be harmful or even fatal to users. As drug
discovery continues to evolve, much lead compound research now includes careful review of its interaction and potential toxicity with mitochondria.
Cytotoxicity and ATP production are measured in cancerous and normal hepatocytes using a known inducer of cellular necrosis. (All figures: BioTek Instruments)
Cell-based mitochondrial assays in microplate format may include
  • mitochondrial membrane potential,
  • total energy metabolism,
  • oxygen consumption, and
  • metabolic activity;
and offer a truer environment for mitochondrial function in the presence of drug compounds compared to isolated mitochondria-based tests.
Combining more than one assay in a multiplex format increases the amount of data per well while decreasing data variability arising from running the assays separately.
The aggregated data also provides a more encompassing analysis of the drug’s effect on mitochondria than a single test.
Human cardiac muscle

Human cardiac muscle (Photo credit: Carolina Biological Supply Company)

English: Non-sustained run of ventricular tach...

English: Non-sustained run of ventricular tachycardia on telemonitoring from a patient with chemotherapy-induced cardiomyopathy. (Photo credit: Wikipedia)

English: Doxorubicin 3D model Русский: Трёхмер...

English: Doxorubicin 3D model Русский: Трёхмерная модель молекулы доксорубицина (Photo credit: Wikipedia)

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Reporter: Aviva Lev-Ari, PhD, RN

Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Part 4:

The Consumer Market for Personal DNA Sequencing

https://pharmaceuticalintelligence.com/2013/01/13/consumer-market-for-personal-dna-sequencing-part-4/

 

Part 3:

Personalized Medicine: Institute Profile – Coriell Institute for Medical Research

Coriell Institute for Medical Research, founded in 1953 and based in Camden, New Jersey, is an independent non-profit research center dedicated to the study of the human genome. Expert staff and pioneering programs in the fields of personalized medicine, cell biology, cytogenetics, genotyping, and biobanking drive our mission.

The emerging field of personalized medicine draws upon a person’s genomic information to tailor treatments and prescription drug dosing to optimize health outcomes. The Coriell Personalized Medicine Collaborative® (CPMC®) research study is seeking to understand the usefulness of genetic risk and pharmacogenomics in clinical decision-making and healthcare management.

Coriell has a distinguished history in cell biology. We are building upon this expertise by playing an important role in induced pluripotent stem (iPS) cell research. Induced pluripotent stem cells are powerful cells which can be made from skin or blood cells, and they are revolutionizing the way human disease is studied and how drugs are developed. Skin cells from a patient diagnosed with heart disease are being genetically reprogrammed into stem cells, and then transformed into beating cardiac cells. Researchers can now examine the heart-diseased cells to better understand the progression of heart disease and develop treatments and cures. Drug efficacy and safety can also be tested in this laboratory environment, providing an efficient model of drug discovery that delivers drugs to patients sooner. This technology, called “disease in a dish,” offers researchers the potential to study the myriad of human diseases, including Alzheimer’s disease, muscular dystrophy, and diabetes.

In addition to pioneering cutting-edge research initiatives, Coriell offers custom research services – including cell culture, cytogenetic analyses, and molecular biology – to the scientific community. Furthermore, Coriell’s Genotyping and Microarray Center is one of the nation’s largest centers, with high-throughput DNA analysis, CLIA-certified genotyping platforms systems from Illumina and Affymetrix.

Essential to the Institute’s support of international scientific research is the Coriell Biobank. From this renowned cell bank, we manage and distribute the world’s most diverse collection of cell lines, DNA, and other biological resources. The Coriell Biobank provided support to the Human Genome Project, a worldwide program to map the entire human genome, and to the International HapMap Project, a project providing an efficient tool to identify disease-causing genes.

The Coriell Cell Repositories provide essential research reagents to the scientific community by establishing, verifying, maintaining, and distributing cell cultures and DNA derived from cell cultures. These collections, supported by funds from the National Institutes of Health (NIH) and several foundations, are extensively utilized by research scientists around the world.

The Business Aspects of the Institute

  • Personalized Medicine

DNA, Genes, and SNPs

What is the CPMC Study?

CPMC Technology

CPMC FAQs

CPMC Advisors and Partners

Stem Cells

Induced Pluripotent Stem (iPS) Cells

iPS Cell Research at Coriell

Biobank Catalog

Working with Coriell

  • Research Services

Overview

Biobanking

Cell Culture

Cytogenetics

Genotyping & Microarray

Molecular Biology

Research Design & Expertise

Stem Cells

Quality at Coriell

  • BioBanking

Overview

What is a Biobank?

How Coriell Banks Cells

Biobank Technology

Biobank Catalog

Working with Coriell

http://www.coriell.org/

http://www.coriell.org/assets/pdfs/discover-winter2012.pdf

http://www.ccr.coriell.org/

http://www.coriell.org/about/coriell-faqs

 

What is the Coriell Institute of Medical Research?

Founded in 1953, Coriell Institute for Medical Research is an independent, non-profit research organization dedicated to the study of the human genome and to supporting national and international research by providing biomaterials from its renowned biobank.

How did the Coriell Institute start?

Lewis L. Coriell, MD, PhD, a virology researcher and pediatrician, recognized the need for scientific research that would translate into better patient care. After seeing how his research helped to bring the Salk vaccine to polio patients across our nation, Dr. Coriell founded the South Jersey Medical Research Foundation. It was renamed the Institute for Medical Research in 1966 to recognize its broader reach, and, in 1985, to honor Dr. Coriell’s retirement, his name was added. For a look at our history, visit our timeline.

http://www.coriell.org/about/our-history

About the Founder

“You set up an experiment to test the theory, and most of the time it’s not the way you thought it would be. But that’s the way you learn. You go from hypothesis to hypothesis. And it’s exciting because that’s the way we learn to treat, to diagnose, and to prevent illness.”

Lewis L. Coriell, MD, PhD
Virologist and Pediatrician
June 19, 1911 – June 19, 2001

Lewis L. Coriell was born in the farming community of Sciotoville, in southern Ohio. While he was still a young child, his family moved to Montana toward more promising agricultural opportunities. It has been written that “the aspects of character, personality, temperament, and intellect that marked Dr. Coriell’s exceptional professional life… can easily be traced to his Montana upbringing.”i

Education and Early Career

Beginning his academic journey at the University of Montana, Lewis Coriell completed undergraduate studies in biology and subsequently earned a master’s degree in bacteriology and immunology in 1936. That same year, he married fellow student Ester Lentz; they would remain by each other’s side for the next 60 years. The newlyweds moved to the University of Kansas so he could pursue doctoral studies in immunology. While there, Dr. Coriell published his first article on an aspect of science he would revolutionize: The storage of cells by freezing them. Lewis Coriell earned his doctorate in 1940 and was awarded his medical degree in 1942. The young researcher was drawn to the field of virology – the study of viruses as they evolve and infect. At this time, bacterial infections presented themselves most often in children. This combination led Dr. Coriell to seek out a residency in pediatrics. As none were immediately available, he chose a cardiology residency at Henry Ford Hospital in Detroit. MI. As it happens, the Coriells’ time in Detroit was brief.

By 1943, World War II was raging and Dr. Coriell was called to service with the United States Army Medical Command’s Biological Research Division at Fort Detrick, MD. It was here that his research in cell cultivation began. After the war, Dr. Coriell began his ideal pediatric residency under Dr. Joseph Stokes, Jr., physician-in-chief at Children’s Hospital of Philadelphia (CHOP).  To his delight, Dr. Stokes placed great emphasis on research and was instrumental in attracting federal funds to research childhood disease at his institution.  The ability to translate research into patient care inspired Dr. Coriell.  He saw how research was essential to the treatment of his patients suffering the devastating effects of viruses like small pox, mumps, and polio.

Adventures in Cell Culture

By the time Dr. Coriell arrived in Philadelphia, virologists knew they had to grow viruses in cell culture to prepare purified viruses for the manufacture of vaccines. However, contamination was rife in the laboratory and proving to be a major obstacle. At CHOP, along with his colleagues, Dr. Coriell perfected the technique to culture human tissue in a sterile host that does not produce its own antibodies. The ability to sustain living human cells in culture, and keep them from being contaminated, led to a key breakthrough in polio research – it enabled scientists to grow the polio virus and work toward the first vaccine.

Moving to Camden and Taking on Polio

By the early 1950’s, an acute infectious disease called polio was spreading from person to person very quickly across the United States, striking fear into citizens, costing children their lives and crippling those who survived. In 1949, Dr. Coriell arrived in Camden, NJ, as medical director of Camden Municipal Hospital, one of the country’s last infectious disease hospitals and home to the majority of the region’s polio patients. In 1951, Dr. Coriell was appointed field director of the Polio Prevention Study and directed the successful gamma globulin field trials.

By 1954, the Salk polio vaccine could be made in large quantities and was ready for human clinical trials. Based on his success shepherding the gamma globulin field trials, Dr. Coriell was chosen by the National Poliomyelitis Foundation to evaluate the Salk polio virus vaccine clinical trials in New Jersey, Pennsylvania, Maryland, and Virginia. The success of the evaluation program led to the release of the Salk vaccine on the national level. Before the trials began in 1955, approximately 20,000 new polio cases were being reported each year. By 1960, cases were reduced to 3,000 per year. By 1979, that number was just 10 each year. Recognizing his contribution, Dr. Coriell received the 1957 International Poliomyelitis Congress Presidential Medal. Soon after, he became chairman of the Committee on the Control of Infectious Diseases of the American Academy of Pediatrics which formulated the vaccination procedures for all children in this critical period.

In 1953, Dr. Coriell initiated a campaign to build the first non-profit academic medical research institute in South Jersey. Under his guidance, the Institute for Medical Research began research in cancer, human cytogenetics, infectious diseases, and methods to improve cell culture techniques. The history of the Institute’s accomplishments included Dr. Coriell’s foresight in calling for the establishment of a central tissue culture bank and cell registry to certify and maintain cell cultures. It began with a partnership with the National Institutes of Health to create the first standardized cell repository. Today, the Institute is home to the world’s most diverse collection of cell lines and DNA samples available to researchers.

Working with his colleague, Dr. Gary McGarrity, Dr. Coriell applied infection control technology – specifically laminar flow – to create the laminar flow hood that is vital to infection control in laboratories, operating rooms, and hospital rooms around the world.

Dr. Coriell’s pioneering techniques for characterizing, freezing, and storing non-contaminated cell cultures in liquid nitrogen constitute one of the greatest contributions to modern human genetics.

Retirement

Dr. Coriell retired in 1985. To honor the occasion, the institute he founded was renamed the Coriell Institute for Medical Research. He remained involved in several ways, as a member of the board and often speaking with groups about the Institute’s history. Following his retirement, Dr. Coriell was elected president of the prestigious College of Physicians of Philadelphia, the oldest medical society in America. Dr. Coriell is the only New Jersey physician to receive this honor.

Dr. Coriell, a pioneering researcher and physician, died on June 19, 2001, in Southern New Jersey. It was his 90th birthday.

A Legacy in Science

Dr. Coriell’s accomplishments in science are indeed many. Perhaps Dr. Coriell’s most enduring legacy was his generosity in knowledge and his ability to bring scientists together to explore research questions and collaborate on solutions. Several important names in science were drawn to join or spend time at the Institute; they included Warren W. Nichols, Ray Dutcher, Richard Mulivor, Etienne Lasfargues, Jesse Charney, Arthur Greene, Daniel Moore, and collaboration with Drs. Albert Levan and Joe Hin Tijo, who first discovered that humans have 46 chromosomes.

Dr. Coriell also created an institute that is a well-respected resident of the Greater Philadelphia region and known as a leader in research worldwide.

Coriell Today

Dr. Coriell’s vision is now our vision. Today, Coriell staff and scientists collaborate on scientific ideas and programs to improve human health.

The Coriell Personalized Medicine Collaborative® research study is studying the utility of using your genetic information to tailor treatments and medications for you. And building on Dr. Coriell’s innovations in cell biology, we are playing an important role in cutting-edge stem cell research to unlock the code of human disease, including Parkinson’s and heart disease. Coriell offers a range of custom research services that have long supported national and international science. In the field of biobanking, Coriell supports research all over the world from its renowned and diverse cell collections.

Our innovation today is a testament to Dr. Coriell’s pioneering past. More importantly, our innovation is a commitment to your future.

i O’Donnell, John. Coriell; The Coriell Institute for Medical Research and a Half Century of Science. Massachusetts: SHP, 2002.

Where is the Coriell Institute located?

Coriell is located at 403 Haddon Avenue, Camden, NJ 08103. For directions, click here
We recommend that you park at 3 Cooper Plaza, a parking garage associated with the hospital, located directly across the street from Coriell. There is also a second hospital parking lot located on Benson Street, which is a block from the Institute.

For what is the Coriell Institute known?

Coriell Institute is a leader in the emerging field of personalized medicine – often called genome-informed medicine – which is the practice of using genetic information to better understand a patient’s risk for disease and response to medications. The Coriell Personalized Medicine Collaborative is a research study designed to study the utility of genetic information in clinical decision-making and patient care.

Coriell is also playing an important role in exploring the promise of induced pluripotent stem (iPS) cell  biotechnologies. [Pluripotent refers to how cells can grow into many different types of cells.] We can take skin cells and reprogram them – essentially turn back time – to behave like a stem cell. These cells can then be triggered, using specific proteins, to become cardiac cells, neurons (brain cells), or insulin-producing pancreatic cells, amongst others. Over the years, Coriell has developed an extraordinary expertise in the culture of human cells, and much of the standard practices in cell culture were developed at Coriell. This includes the techniques for freezing and thawing cells, and sterile handling of cultures. As a result of our cell biology expertise, scientists from every major research center in the world draw upon the Coriell Cell Repositories, maintained in the world’s leading biobank, which contains cell lines and DNA representing approximately 650 diseases.

Who is on the Coriell Institute staff?

Coriell is home to approximately 120 scientific and operational staff. Michael Christman, PhD, is Coriell’s President and CEO; he is an expert in genomics and genetics.  Joseph L. Mintzer is Coriell’s Executive Vice President and COO and manages the fiscal and operational aspect of the institute. Meet the rest of the Coriell leadership team here.

Who is on the Coriell Institute Board of Trustees?

Coriell is guided by a diverse Board of Trustees that includes corporate, medical, financial, and philanthropic leaders. Chairman of the Coriell Board is Robert P. Kiep III. Learn more about the Coriell Board of Trustees here.

How is Coriell Institute funded?

Coriell Institute has an annual operating budget of $17 million, about $11 million of which comes from federally- and state-funded grants and contracts. Private and corporate philanthropy provides the seed money to initiate new programs in science at Coriell – science that has the opportunity to advance discoveries in research which may not be occurring at other research institutes.

How can I support the research mission of Coriell Institute?

While the majority of Coriell’s operating revenue is derived from federally- and state-funded grants and contracts, the Institute also relies on private, foundation, and corporate philanthropy. Your support can advance the emerging field of personalized medicine to improve the practice of medicine. Your support also allows Coriell to pursue and support research in adult stem cell biology and genomics seeking to unlock the code of human disease. 
There are many ways to give to Coriell: Outrights gifts, through your workplace giving programs, planned giving, volunteering your time and expertise, or attending or hosting a Coriell event. Visit our fund development page to learn more about how you can support scientific research.

How does Coriell Institute support international research?

The Coriell Cell Repositories offers essential research materials to the scientific community by establishing, verifying, maintaining, and distributing cell cultures and DNA. Since the first NIH-sponsored repository was established in 1964 – Coriell has distributed hundreds of thousands of cell lines and DNA samples to researchers in 64 countries. More than 7,000 peer-reviewed papers have been published citing almost 12,000 Coriell Repository samples.

What research services does Coriell Institute provide? 
Coriell offers several best-in-class custom research services.

Coriell’s Genotyping and Microarray Center – one of the nation’s largest centers and CLIA-certified in 48 states – is a high-capacity facility with high-throughput systems from Affymetrix and Illumina.

The Coriell Institute Cytogenetics Laboratory is a state-of-the-art facility that combines conventional and molecular cytogenetic analyses with copy number and loss of heterozygosity (LOH) analyses by microarray. The laboratory is equipped with a network of five Applied Spectral Imaging work-stations that are used to perform G-banded karyotyping, and Fluorescent In Situ Hybridization (FISH).

Coriell also offers many preparative and diagnostic nucleic acid and molecular biology services, all subject to extensive quality controls.

And, the Coriell biobank is regarded as the most diverse collection of cell lines and DNA available to the international research community.

Does Coriell Institute engage in gene therapy or stem cell clinical trials?

Coriell Institute does not pursue research using human embryonic stem cells, nor do we conduct clinical trials on stem cell technologies. If you are interested in gene therapy or stem cell-related clinical trials, please visit http://www.clinicaltrials.gov.

What education does Coriell offer?

Coriell offers a course in cell culture: Advanced biology coupled with the history, theory, and techniques of maintaining live cells in long-term culture is offered to students.

Coriell also invites a limited number of motivated students into the Institute to participate in a Summer Experience program to gain insight into the workings of an independent research institute

How can I stay informed on what is happening at Coriell Institute?

Sign up for our email updates and you’ll receive periodic research news, notable donations, and upcoming events. Visit our Media Center regularly to read the latest news articles and Coriell press releases.

How can I get a quick overview of Coriell Institute?

Read our Coriell Fast Facts for a basic introduction to the Institute. For more information, explore the About section of our website.

Are Coriell Institute scientists and staff available for speaking engagements?

As their schedules permit, Coriell’s scientific and operational staffs enjoy the opportunity to highlight the work occurring at Coriell. Many hold joint faculty appointments at our region’s universities and teach an array of topics from business management and healthcare policy to the science of cell culture and stem cell research.

Coriell also participates in several outreach programs each year, including science festivals and conferences. We also host tours of our laboratories for business and governmental leaders and middle school and high school students.

16. Is Coriell Institute affiliated with Cooper Medical School of Rowan University?
Yes; Coriell is looking forward to welcoming the new medical school and will be integral in teaching genetics and genomics to the next generation of healthcare providers.

Fig3a-200

The Power of Stem Cell Science

The promise of stem cell research lays in its application in understanding the progression of human disease, the ability to cure disease and reverse injury, and to better target therapies to optimize our health outcomes. Induced pluripotent stem (iPS) cell technology has the ability to revolutionize the way human disease is studied. Creating iPS cell lines from various rare and common disease states, as well as from various populations, will open the doors for pre-clinical research studies.

Fig3b-200

Let Our Expertise Make Your Research a Success

Coriell offers a range of custom research services that have long supported national and international science. Whether you are requesting a cell line for your research studies or submitting DNA samples for genotyping analysis, Coriell is committed to providing you with flexible, innovative, and results-oriented research services. Our laboratories are built to foster scientific collaboration, and your research will benefit from this collaborative environment.

Coriell’s Biobank and Cell Culture Laboratory have established the gold standard in the cryopreservation of biomaterials and the capacity to support varied research worldwide. The diverse collections of biological specimens managed by Coriell offer the scientific community the highest quality specimens, which are necessary for successful research endeavors. Since the first repository – a National Institutes of Health collection – was established at Coriell in 1964, hundreds of thousands of cell lines and DNA samples have been distributed to researchers in 64 countries; more than 7,000 peer-reviewed papers have been published citing almost 12,000 biospecimens from the Coriell Biobank.

Fig3c-200

Making Medicine Personalized for You

Our health is determined by many factors: the genetics we inherit; our innate personal traits of race, age and gender; our individual behavior; our family and community networks; and at the macro level, our economic, cultural, and environmental conditions. These factors are different for every person and will change over their lifespan. So too is a person’s experience with disease and how they respond to drugs or other medical interventions. Personalized medicine intends to make medical treatment as individual as the biology of one’s disease.

Personalized medicine has the potential to offer patients and their doctors several advantages, including:

The ability to make better informed clinical decisions.

A higher probability of desired health outcomes by using better-targeted therapies.

The reduced probability of adverse reactions from medications and treatments.

A focus on prevention and prediction of disease, rather than reaction to it.

Earlier disease intervention.

Reduced healthcare costs.

Fig3d-200

Preserving cells today for research tomorrow

Dr. Lewis Coriell’s pioneering techniques for characterizing, freezing, and storing cell cultures in liquid nitrogen constitute one of the greatest contributions to modern human research. Today, the Coriell Biobank is regarded as the most diverse collection of cell lines and DNA available to the international research community. In addition to these high-quality biospecimens, Coriell also maintains tissue, plasma, serum, urine, and cerebrospinal fluid.

Few organizations have the history of innovations in repository science that have been developed and implemented at Coriell. For nearly 60 years, Coriell has set the standard in biobanking services, including the experimental design, collection, processing, distribution, cryogenic preservation, and information management of human biomaterials used in research. By developing and maintaining biorepositories as national and international resources for the study of human diseases, aging, and neurological disease, Coriell is committed to providing the scientific community with well-characterized, cell cultures and DNA preparations, annotated with rich phenotypic data.

Catalog Collections

NIGMS Human Genetic Repository 
The Human Genetic Cell Repository, sponsored by the National Institute of General Medical Sciences, provides scientists around the world with resources for cell and genetic research. The samples include highly characterized cell lines and high quality DNA. Repository samples represent a variety of disease states, chromosomal abnormalities, apparently healthy individuals and many distinct human populations.

NINDS Human Genetics DNA and Cell Line Repository 
The National Institute of Neurological Disorders and Stroke is committed to gene discovery, as a strategy for identifying the genetic causes and correlates of nervous system disorders. The NINDS Human Genetics DNA and Cell Line Repository banks samples from subjects with cerebrovascular disease, epilepsy, motor neuron disease, Parkinsonism, and Tourette Syndrome, as well as controls.

NIA Aging Cell Repository 
Sponsored by the National Institute on Aging (NIA), the AGING CELL REPOSITORY, is a resource facilitating cellular and molecular research studies on the mechanisms of aging and the degenerative processes associated with it. The cells in this resource have been collected over the past three decades using strict diagnostic criteria and banked under the highest quality standards of cell culture. Scientists use the highly-characterized, viable, and contaminant-free cell cultures from this collection for research on such diseases as Alzheimer disease, progeria, Parkinsonism, Werner syndrome, and Cockayne syndrome.

NHGRI Sample Repository for Human Genetic Research 
The National Human Genome Research Institute (NHGRI) led the National Institutes of Health’s (NIH) contribution to the International Human Genome Project, which had as its primary goal the sequencing of the human genome. This project was successfully completed in April 2003. Now, the NHGRI’s mission has expanded to encompass a broad range of studies aimed at understanding the structure and function of the human genome and its role in health and disease.

American Diabetes Association, GENNID Study 
The purpose of the American Diabetes Association (ADA), GENNID Study (Genetics of non-insulin dependent diabetes mellitus, NIDDM) is to establish a national database and cell repository consisting of information and genetic material from families with well-documented NIDDM. The GENNID Study will provide investigators with the information and samples necessary to conduct genetic linkage studies and locate the genes for NIDDM.

The Autism Research Resource 
The State of New Jersey funded the initiation of a genetic resource to support the study of autism in families where more than one child is affected or where one child is affected and one demonstrates another significant and related developmental disorder. This resource now receives continuing support from the Coriell Institute for Medical Research. An open bank of anonymously collected materials documented by a detailed clinical diagnosis forms the basis of this growing database of information about the disease.

IPBIR Repository 
The purpose of the IPBIR – Integrated Primate Biomaterials and Information Resource is to assemble, characterize, and distribute high-quality DNA samples of known provenance with accompanying demographic, geographic, and behavioral information in order to stimulate and facilitate research in primate genetic diversity and evolution, comparative genomics, and population genetics.

HD Community BioRepository 
HD Community BioRepository is a secure, centralized repository that stores and distributes quality-controlled, reliable research reagents. Huntingtin DNAs are now available and antibodies, antigenic peptides, cell lines, and hybridomas will be added soon.

USIDNET Repository 
The USIDNET DNA and Cell Repository has been established as part of an NIH-funded program – the US Immunodeficiency Network (www.usidnet.org) – to provide a resource of DNA and functional lymphoid cells obtained from patients with various primary immunodeficiency diseases. These uncommon disorders include patients with defects in T cell, B cell and/or granulocyte function as well as patients with abnormalities in antibodies/immunoglobulins, complement and other host defense mechanisms.

CDC Cell and DNA Repository 
The Genetic Testing Reference Material Coordination Program of the Centers for Disease Control and Prevention (CDC) and the Coriell Institute for Medical Research announce the availability of samples derived from transformed cell lines for use in molecular genetic testing. The DNA samples prepared from these reference cell lines are available through the Coriell Cell Repositories. Diseases include cystic fibrosis (CF), 5′ 10′ methylenetetrahydrofolate reductase deficiency (MTHFR), HFE-associated hereditary hemochromatosis, Huntington disease (HD), fragile X syndrome, Muenke syndrome, connexin 26-associated deafness, and alpha-thalassemia.

Leiomyosarcoma Cell and DNA Repository 
The Leiomyosarcoma Cell and DNA Repository has been established with an award from the National Leiomyosarcoma Foundation. This foundation provides leadership in supporting research of Leiomyosarcoma, improving treatment outcomes of those affected by this disease as well as fostering awareness in the medical community and general public.

COHORT Project 
The Cooperative Huntington’s Observational Trial Repository has been established as a resource for the discovery of information related to Huntington’s disease and its causes, progressioin, treatments, and possible cures. This is a growing bank for DATA and SPECIMENS to accelerate research on Huntington’s disease.

YERKES Repository 
The Yerkes National Primate Research Center of Emory University is an international leader in biomedical and behavioral research. For more than seven decades, the Yerkes Research Center has been dedicated to advancing scientific understanding of primate biology, behavior, veterinary care and conservation, and to improving human health and well-being.

NEI-AREDS Genetic Repository 
The Age-Related Eye Disease Study was designed to learn about macular degeneration and cataract, two leading causes of vision loss in older adults. The study looked at how these two diseases progress and what their causes may be. In addition, the study tested certain vitamins and minerals to find out if they can help to prevent or slow these diseases. Participants in the study did not have to have either disease. (Enrollment was completed in January 1998.) Eleven medical centers in the United States took part in the study, and more than 4,700 people across the country were enrolled in AREDS. The study was supported by the National Eye Institute, part of the Federal government’s National Institutes of Health. The clinical trial portion of the study also received support from Bausch & Lomb Pharmaceuticals and was completed in October 2001. Learn about the results of the clinical trial on the National Eye Institute’s website: http://www.nei.nih.gov/amd/.

The Wistar Institute 
The Wistar Institute collection at Coriell contains cell lines that have been developed by Wistar scientists. These materials are offered for non-commercial research conducted by universities, government agencies and academic research centers. The Wistar Institute collection currently contains a group of hybridomas that produce monoclonal antibodies that are useful in influenza research and vaccine development. Melanoma cell lines, derived from patients with a wide range of disease ranging from mild dysplasia to advanced metastatic cancer, will be added shortly. More information on The Wistar Institute, its research and scientists can be found at www.wistar.org.

J. Craig Venter Institute Human Reference Genome (HuRef) 
The Human Reference Genetic Material Repository makes available DNA from a single individual, J. Craig Venter, whose genome has been sequenced and assembled. The DNA samples are prepared from a lymphoblastoid cell line established at Coriell Cell Repositories from a sample of peripheral blood. The DNA samples are available in 50 microgram aliquots. The lymphoblastoid cell line is not available for distribution..

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