Human Heart in a Dish: Novel In-Vitro Cardiotoxicity Testing Platform
Tuesday, November 17, 2015
3:00 p.m.-4:00 p.m.
FDA White Oak Location, Bldg. #2 room 2031
301 405 0285
José Jalife, M.D., University of Michigan
To view the recording link: https://collaboration.fda.gov/p8rhcibu7t3/
Dr. Jalife completed his M.D. at the Universidad Nacional Autónoma de México in 1972. After clinical training in Spain, he moved to the United States to work as a postdoctoral fellow at the Upstate Medical Center in Syracuse, NY, and the Masonic Medical Research Laboratory in Utica, NY. He joined the Department of Pharmacology, Upstate Medical University, as a member of the faculty in 1980 and became its Chairman in 1988. In January of 2008, he was recruited by the University of Michigan to his present position as Professor of Internal Medicine and the Cyrus and Jane Farrehi Professor of Cardiovascular Research and Professor of Molecular & Integrative Physiology. Dr. Jalife enjoys an international reputation as a leader in the study of cardiac arrhythmias. His work has increased the understanding of the fundamental mechanisms of atrial fibrillation, ventricular tachycardia/fibrillation and sudden cardiac death. He has published more than 320 original papers and review articles, and has edited/authored fifteen books, including the internationally acclaimed Cardiac Electrophysiology: From Cell to Bedside, now in its sixth edition. Dr. Jalife has served the US National Institutes of Health in many capacities, including past membership in Research Committee-A, the Cardiology Advisory Committee, the Cardiovascular Study Section, (CVA), and the ESTA Study Section of the National Heart Lung and Blood Institute. He has also been a member of multiple site visit committees and ad-hoc review committees of the NHLBI and the American Heart Association. Throughout his career Dr. Jalife has trained more than 100 scientists for research careers at nearly all educational levels, including pre-doctoral fellow for PhD degrees, medical student, post-doctoral trainees, medical residents and clinical fellows. In 2001 Dr. Jalife was awarded the Distinguished Scientist Award of the American College of Cardiology. Other accolades include the Distinguished Scientist Award of the Heart Rhythm Society, the Lucian Award for Research in Circulatory Diseases from McGill University, the President's Award for Research at SUNY Upstate Medical University, the Professor Pierre Rijlant Award from the Académie Royale de Médecine de Belgique in Brussels, Belgium, the State University of New York Chancellor's Award for Excellence in Scholarship and Creative Activities, the Mirowski Award of Excellence in the field of Clinical Cardiology and Electrophysiology and the Arthur C. Guyton Distinguished Lecturer ward from the Association of Chairs of Departments of Physiology. Dr. Jalife is an honorary member of the Mexican National Academy of Medicine, Fellow of the American Heart Association, Fellow of the Heart Rhythm Society and member of the Association the American Association of Physicians; between 2010 and 2012 he served as President of the Cardiac Electrophysiology Society. In 2015 he was awarded a Doctor Honoris Causa by the University of Valencia in Spain.
Human Heart in the Dish: Novel In-Vitro Cardiotoxicity Testing Platform
Many potentially good drugs are removed from further development and never reach patients because they are found to be potentially cardiotoxic. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a reliable assay for pre-clinical drug screening. However, hiPSC-CMs used to date demonstrate immature structural and electrophysiological properties not representative of the adult myocardium. Furthermore, besides multi-electrode arrays, there is a lack of high throughput platforms for the assessment of electrophysiological function in hiPSC-CMs. We have generated an unlimited supply of hiPSC-CMs monolayers that can be cryopreserved, thawed, and cultured. In addition, we have identified an optimal approach for significant electrophysiological and structural maturation of hiPSC-CMs. The resulting hiPSC-CM monolayers have impulse propagation velocities ~2X faster than previously reported (up to ~50 cm s-1), mature cardiomyocyte action potential profiles and physiologic hypertrophic growth. They also express key mature sarcolemmal (Kir2.1) and myofilament markers (cTroponin I). Furthermore, we have designed a 96-well high-throughput action potential duration (APD) screening platform using mature hiPSC-CMs plated as monolayers. The approach can accurately predict eventual cardiotoxicity in humans. The utility of the system for in-vitro drug screening has been validated using compounds with known risk for APD prolongation that can lead to life-threatening arrhythmias in vivo. Altogether, the approach should drive the use of hiPSC-CMs into mainstream pre-clinical toxicity testing.
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