Session Descriptions

Andrew Plump, M.D, Ph.D.
Executive Director, Cardiovascular Disease Franchise, Merck & Co. 

Genomic Approaches to Developing Atherosclerosis Biomarkers  

Summary: Emerging imaging technologies and novel circulating biomarkers offer promise in driving the development of new anti-atherosclerosis therapies; however, the ultimate utility of imaging and circulating biomarkers in drug development may not be realized for 5 or more years.  Pharmaceutical companies have pipelines with many potential new therapies to treat atherosclerosis, but have essentially no means for deciding which of these therapies should be brought forward into long and costly outcome studies.  In short there is a need to build tools that allow for biomarker based decision making in early clinical development.  Evidence suggests that the biology of atherosclerosis can be studied directly in human plaque.  We are studying an array of genomic and candidate biomarkers in lower extremity peripheral atherectomy and carotid endarterectomy samples in cross-sectional and drug intervention trials to better understand the biology of atherosclerosis and to study the pharmacodynamic effects of drug interventions in order to drive the development of potentially novel anti-atherosclerosis therapies.  In addition, these efforts will link with genome wide association studies to define disease causal pathways from which one can concurrently identify new atherosclerosis therapeutic targets, biomarkers for these new targets, and the responder patient populations. 

 

Timothy McCaffrey, Ph.D.
Professor & Vice-Chair, Department of Biochemistry and Director, McCormick Genomics Center,
The George Washington University School of Medicine 

Identifying Targets for Therapy Via Genomic Strategies

Summary: The inappropriate survival of cells in an injured or stressed artery contributes to atherosclerotic plaque progression, while apoptosis in the fibrous cap of lesions can lead directly to myocardial infarction and stroke.  Genomic-scale transcript profiling of human carotid artery plaque cells with known sensitivity or resistance to fas-induced apoptosis identified candidate genes involved in lesion cell apoptosis. Retroviral overexpression of these candidate genes indicated that most were not causally related, but that Bcl-XL conferred complete resistance to apoptosis induced by fas ligation. Resistant cells failed to efficiently activate caspase 8, an effect which was also observed in Bcl-XL transfected cells.  Small-molecule Bcl-2/XL inhibitors and siRNA knockdown of Bcl-XL markedly sensitized resistant cells to apoptosis, and partially restored caspase 8 activation. Bcl-XL appears to modulate lesion cell apoptosis by suppressing mitochondrial amplification of caspase activation loops.  The results may have direct implications for controlling plaque instability/progression, and identifies a new class of small-molecules to inhibit restenosis.

 

Michael R. Bristow, M.D., Ph.D.
Professor of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Chairman and Chief Science and Medical Officer, ARCA Discovery 

Genomics and Heart Failure 

Summary: There are three general ways in which genomics, or variations in gene expression, can influence the development, progression and therapeutic response of heart failure (Bristow MR, Taylor MRG. Alterations in myocardial gene expression as a basis for cardiomyopathies and heart failure. In: Heart failure: molecules, mechanisms and therapeutic targets. Novartis Found Symposium 73-83, 2006.). The first is a gene mutation, by definition occurring at a prevalence of cardiomyopathy. The second is polymorphic variation in gene structure, by definition occurring at a prevalence of ³1.0%, resulting in a change in gene function that can affect the development of heart failure, heart failure natural history, or therapeutic response to therapy. The third way in which genomics can affect heart failure is via “functional genomics,” or altered regulated expression of wild type/major variants of genes, resulting in changes in the progression of pathologic hypertrophy or contractile function, or response to therapy. This presentation will focus on the targeting of polymorphic variation as a means of improving drug therapy for chronic heart failure. 

  

Raymond L. Woosley, M.D., Ph.D.
President and CEO, The Critical Path Institute 

Applications of Pharmacogenomics to Improve Cardiovascular Drug Safety 

Summary:  For almost two decades, clinical investigators have identified associations between genetic variation and response to pharmacologic agents.   The increasing availability of genetic diagnostic tests at the point of care and at relatively low cost are factors enabling the clinical application of genomic information.  Genomic assays are now available that can predict the genetic variance that determines metabolic clearance of warfarin by Cytochrome P450 2C9 and the VKORC1 receptor sensitivity to warfarin.  DNA microarrays have been developed that can identify patients with deficient elimination that could place them at risk for toxic reactions.  Excessive QT prolongation remains a serious toxicity risk for many drugs.  Genetic tests that can predict drug exposure and drug sensitivity have the potential of reducing the risk of drug-induced arrhythmias.  However, major barriers remain in the broad application of these genetic tests.

 

Elizabeth G. Nabel, M.D.
Director, National Heart, Lung, and Blood Institute (NHLBI) 

Genomics and Coronary Artery Disease 

Summary: Personalized medicine is the use of molecular analysis to better manage a patient’s disease or predisposition to disease in order to achieve optimal clinical outcomes by helping physicians and patients choose the approaches best suited to the patient’s genetic and environmental profile.  Dr. Nabel will discuss exciting advances in personalized medicine and coronary heart disease supported by the National Heart, Lung, and Blood Institute.

  

Paul Hwang, M.D., Ph.D.
Principal Investigator, Cardiology Branch
National Heart, Lung, and Blood Institute 

Markers and Mediators of Atherosclerosis Revealed by Genomic Analysis of Circulating Cells 

Summary: One limitation for gene expression studies in translational cardiovascular medicine has been access to disease-associated patient tissues.  As a cardiovascular tissue surrogate, we used freshly isolated blood mononuclear cells from patients undergoing carotid endarterectomy due to atherosclerotic stenosis and from matched normal subjects.  Using this approach, we found that the mRNA levels of the Finkel-Biskis-Jinkins osteosarcoma (FOS) gene in circulating monocytes correlated with atherosclerosis severity in patients and with HMG CoA reductase inhibitor (statin) therapy in normal subjects.  Although the clinical utility of our finding remains open, our study also revealed new insights into the genetic mechanisms regulating inflammation in atherosclerotic plaques.

  

James J. Devlin, Ph.D.
Director, Cardiovascular Research, Celera 

Gene Variants Predict Risk of CHD and Clinical Benefit from Statin Therapy 

Summary: Gene variants associated with risk of CHD have been identified in case-control studies and confirmed in population-based prospective studies. However, uncertainty regarding the mechanism by which these gene variants increase risk of CHD may lead to uncertainty regarding whether this increased risk can be compensated for by statin therapy, a therapy thought to reduce global risk of CHD. We found that benefit from statin treatment is actually greater in carriers of some risk variants than in noncarriers by investigating these variants in genetic studies of placebo controlled statin trials.

  

Robert Roberts, M.D.
President and CEO University of Ottawa Heart Institute 

Genotypic and Phenotypic Markers of CAD 

Summary: The pursuit of genes for single gene disorders has had a remarkable success.  However, the search for genes responsible for common disorders such as coronary artery disease, hypertension and cancer has only just begun.  The technology to perform genome wide association studies only became available less than two years ago.  This technology, making it possible to perform genome wide scans with millions of markers, is now available and results for several diseases appear very promising.  We initiated a genome wide scan for coronary artery disease utilizing the 500K array and in a collaborative effort with investigators from the University of Texas, Denmark and others identified the first common locus for coronary artery disease.  This has now been confirmed by several independent groups in a total of over 50,000 individuals.  The details of this locus located at 9p21and future plans for GWA in heart disease will be discussed. 

  

Federico Goodsaid, Ph.D.
Genomics Group, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation & Research 

Pilot Process for Biomarker Qualification at the FDA

Summary: Biomarker qualification is needed to encourage the application of new biomarkers in drug development and regulatory review. This application requires a clear regulatory path to a consensus on their qualification. The FDA is testing a Pilot Program for Biomarker Qualification in order to develop a path for qualification of biomarkers in the context of their intended use in drug development and regulatory review. A number of biomarker qualification requests are currently under consideration through this process. These cases have already shown the power of this process as well as areas where this process could be improved in the future.