Stem Cells in Toxicity Testing


November 4, 2010
1:30 – 3:00 pm EST

 

Agenda

1:30-1:35 Welcoming Remarks from Webinar Moderator

1:35-2:00 Integration of Stem Cell Derived Cells into Safety and Toxicity Testing 
Sandra Engle, Ph.D., Senior Principal Scientist, Genetically Modified Models Research Center of Emphasis, Pfizer, Inc.
Safety and toxicology issues of drug candidates contribute to approximately 30% of drug attrition rates. With an increasingly risk-adverse regulatory environment, possible safety issues associated with potential therapies have become an increasingly difficult hurdle to overcome in the registration process. The 2007 NAS Report “Toxicity Testing in the 21st Century: A Vision and a Strategy” suggested the idea that toxicity testing was poised for a paradigm shift in which advances in toxicogenomics, bioinformatics, systems biology and epigenetics would largely allow the replacement of animal studies with in vitro methods. Central to this idea is the development of cellular models which better predict human physiology. The properties of human adult stem cell and pluripotent stem cells make them an attractive cell source for developing these in vitro models, and expectations have been high. Progress, however, has been slow. Challenges with generating cells of the appropriate purity with the appropriate characteristics have meant that studies have only recently begun to compare the response of these cells to established in vitro cell models. This talk will examine ways in which stem cell derived cells may be used to address safety and toxicity in drug development.

2:00-2:25 SC4SM Predictive Toxicology Consortium: Progress and Challenges
Frank W. Bonner, Ph.D., Chief Executive Officer, Stem Cells for Safer Medicines Ltd.
The attrition of new drugs in development due to toxicity remains high and is a significant factor impacting upon the overall productivity of pharmaceutical R&D. Consequently, there is ongoing effort to incorporate safety testing models earlier into the drug discovery/development process. There is further scope to introduce new models which are practicable (robust, reproducible, etc.) and have improved throughput and predictivity. Stem Cells for Safer Medicines, SC4SM, is a public-private partnership that was established following a recommendation of the UK Stem Cell Initiative to develop predictive toxicology tools from stem cell lines. The company operates as a consortium of industrial and academic partners and is focused upon the development of models using both hepatocyte and cardiomyocyte-like cells derived from human embryonic stem cells. The objective is to define the conditions that will enable consistent differentiation of homogeneous and well characterized cell lines which can be validated using an extensive library of compounds in order to demonstrate their potential utility as predictive toxicology screens to reduce risk in drug development. The presentation will describe the aims of the consortium in more detail, discuss the progress that has been made to date and identify the key objectives and challenges of the next phase of development of the research program.

2:25-2:50 A Lethal Human Cardiac Arrhythmia is Faithfully Recapitulated In Vitro
Bruce R. Conklin, M.D., Senior Investigator, Gladstone Institute of Cardiovascular Disease; Professor, Medicine, University of California, San Francisco
The generation of human induced pluripotent stem (iPS) cells from adult human dermal fibroblasts provides an exciting opportunity to create disease-specific pluripotent stem cells and model human genetic diseases. Here we demonstrate that iPS cell lines from patients with the cardiac arrhythmia, long QT syndrome type 2 (LQT-2), yield cardiomyocytes that recapitulate the potassium channel currents and prolonged action potential duration (APD) characteristic of LQT syndrome. The iPS cells derived from LQT-2 patient fibroblasts (LQT-2 iPS cells), which has known mutation as LQT-2, were retrovirally reprogrammed using the genes, Sox2, Oct3/4, Klf4 and c-Myc. These cell lines demonstrate silencing of the exogenous genes and expression of pluripotency markers. The LQT-2 iPS cells can differentiate into cell types of all three embryonic germ layers including beating cardiomyocytes expressing cardiac troponin T (cTnT) and β-myosin heavy chain (βMHC). The action potential durations of LQT iPS-derived cardiomyocytes are significantly prolonged as measured by single cell patch-clamp and optical mapping. E4031 loading also reveals the characteristic feature of LQT-2 in LQT iPS-derived cardiomyocytes. In conclusion, our results show that iPS cell technology can faithfully recapitulate the LQT phenotype in vitro and is a powerful platform for further basic research investigation, drug discovery and toxicology screening.

2:50-3:00 Q&A with the Speakers

SPEAKER BIOGRAPHIES:

Frank W. Bonner, Ph.D., FBTS, is Chief Executive of Stem Cells for Safer Medicines, a public-private partnership which is focussed upon developing stem cell assays for predictive toxicology.  Frank has over 25 years of experience in toxicology and non-clinical drug development. He is a Fellow of the British Toxicology Society, Past President of the Society and currently serves on the Scientific Advisory Boards for a number of technology companies. In 2009, he was appointed Visiting Professor in the Institute of Cellular Medicine, University of Newcastle where he is involved in postgraduate teaching in Medical and Molecular Biosciences.

Bruce R. Conklin, M.D., is a Senior Investigator at the Gladstone Institute of Cardiovascular Disease.  He is also a Professor of Medical Genetics and Cellular and Molecular Pharmacology at the University of California, San Francisco. Dr. Conklin received his A.B. in Public Health from the University of California, Berkeley, and completed his medical training at the Case Western Reserve University School of Medicine. During medical school he spent two years as a Howard Hughes Medical Institute research scholar in the laboratory of Nobel Laureate Julius Axelrod, Ph.D., at the National Institute of Mental Health. Dr. Conklin completed his residency in internal medicine at Johns Hopkins Hospital, and he did his postdoctoral training in molecular pharmacology with Henry Bourne, M.D., at UCSF.  Dr. Conklin established his laboratory at Gladstone in 1995. At Gladstone, Dr. Conklin has been the founding Director of the Gladstone Stem Cell Core, the Gladstone Genomics Core Laboratory, and helped establish the Gladstone-CIRM Research Scholars program. Dr. Conklin is on the advisory board of organizations and companies such as Cytoscape, and iPierian. Dr. Conklin’s honors include the 2008 Scientific American-50 Award, and being a member of the American Society for Clinical Investigation. Dr. Conklin’s laboratory studies the mechanisms by which hormone receptors direct the development and function of complex tissues, including those found in the cardiovascular system. The focus of his research is on the largest known family of receptors for hormones and drugs, the G protein–coupled receptors (GPCRs), which include over 700 human genes. His research combines genetic knockouts, designer GPCRs and bioinformatics techniques in order to gain a basic understanding of hormone signaling in embryonic stem (ES) cells and induced pluripotent (iPS) cells.

Sandra Engle, Ph.D., is a Senior Principal Scientist in the Genetically Modified Models (GeMM) Research Center of Emphasis at Pfizer, Inc. She received a B.A. in biology from Ball State University and a Ph.D. in Medical and Molecular Genetics from Indiana University School of Medicine. Dr. Engle has been growing, characterizing and differentiating mouse embryonic stem cells since the late 1980’s. In her current role, she is responsible for the generation of mouse and human pluripotent stem cell models. Her activities include generating and characterizing induced pluripotent cells from pre-clinical species and humans as well as optimizing in vitro differentiation protocols that deliver terminally differentiated cell types with defined functional characteristics in a format amenable to medium to high throughput plate-based screening assays for both drug discovery and toxicity testing.


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