Agenda

Adeno-associated virus vector-based in vivo gene therapy – State of the art, challenges and strategies for mitigation

Guangping Gao, PhD, Horae Gene Therapy Center & Weibo Li Institute for Rare Diseases Research, University of Massachusetts Medical School.

This presentation will provide an overview on the key principles, state of the art, challenges, and potential strategies to mitigate in AAV in vivo gene therapy. The presentation will also showcase AAV capsid discovery and engineering to modulate target tissue tropism, therapeutic gene expression cassette design and optimization to enhance transduction efficiency, tissue/cell type specify and reduce immunogenicity, and examples of AAV gene therapy development: from proof-of-concept preclinical studies to first-in-human clinical evaluation.

Speaker Short Bio

 Guangping Gao, PhD is the Director, Horae Gene Therapy Center and Viral Vector Core, Co-Director, Li Weibo Institute for Rare Diseases Research, Professor of Microbiology and Physiological Systems, Penelope Booth Rockwell Professor in Biomedical Research, University of Massachusetts Medical School; Elected fellows, both the US National Academy of Inventors  (NAI) and American Academy of Microbiology; Past president, American Society of Gene and Cell Therapy.

Dr. Gao is an internationally well recognized gene therapy researcher, instrumental in the discovery and characterization of a new family of adeno-associated virus (AAV) serotypes, which revitalized the field of gene therapy. Dr. Gao’s research primarily focuses on gene therapy platform technologies and product development.

Dr. Gao has published more 310+ research papers, 6 book chapters, and 5 edited books. Dr. Gao holds 191 patents with 401 more patent applications pending.  He serves as Executive Editor-In-Chief of Human Gene Therapy, Senior Editor of the Gene and Cell Therapy book series, Associate Editor of Signal Transduction and Targeted Therapy, and on Editorial Boards of several other gene therapy and virology journals. Dr. Gao was ranked as the World Top 20 Translational Researchers by Nature Biotechnology.

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Adam J. Engler is a Professor and Vice-Chair of Bioengineering at UC San Diego, where he has been on the faculty since 2008. He also is a resident scientist at the Sanford Consortium for Regenerative Medicine and Associate Director of the Medical-Scientist Training Program (MSTP).

Dr. Engler previously trained with Dr. Dennis Discher at the University of Pennsylvania, where he earned his PhD studying how ECM stiffness regulated stem cell fate. He also trained as a postdoc with Dr. Jean Schwarzbauer at Princeton University’s Department of Molecular Biology where he studied the mechanics of extracellular matrix assembly.

Dr. Engler’s current research focuses on how physical and chemical properties of the niche influence or misregulate cell function and modify genetic mechanisms of disease. In particular, his lab studies this phenomenon in the context of cardiovascular diseases and cancer. To accomplish this, his lab makes natural and synthetic matrices with unique spatiotemporal properties to mimic niche conditions, improve stem cell behavior and commitment in vitro, or direct them for therapeutic use in vivo. He currently has published over 100 manuscripts with an H-index of 52, holds 3 patents, and has a start-up company focused on stem cell research products.

Dr. Engler has received numerous awards in recognition of this research, including young investigator or mid-career awards from International Society for Matrix Biology (2008), Biomedical Engineering Society (2008), American Society of Matrix Biology (2014), American Society of Mechanical Engineering (2015), and American Society for Engineering Education (2018). Dr. Engler is a 2018 fellow of the American Institute for Biomedical Engineering and recipient of an NIH New Innovator Award grant (2009).

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disease caused by a CTG microsatellite repeat expansion in the DMPK gene, leading to the expression of pathogenic expanded CUG-repeat (CUGexp) containing RNA. The toxic CUGexp RNA causes disease by disrupting the activities of RNA binding proteins that regulate postnatal RNA processing ultimately resulting in expression of fetal protein isoforms of a subset of genes in adult tissues. Cardiac involvement affects 50% of individuals with DM1 primarily due to conduction abnormalities and arrhythmias causing 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease including cardiac conduction delays, spontaneous and inducible supraventricular arrhythmias, nuclear RNA foci with colocalization of the muscleblind RNA binding protein and alternative splicing defects. Importantly, both electrophysiological and molecular features were reversible upon loss of CUGexp RNA expression. The results identify potential mechanisms contributing to cardiac pathogenesis and demonstrate the utility of a reversible cardiac DM1 mouse model to facilitate development of targeted therapeutic approaches.

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Dr. Roubenoff received his MD from Northwestern University and trained in Internal Medicine and Rheumatology at the Johns Hopkins Hospital, where he was Chief Resident in Medicine. He completed concurrent fellowships in Rheumatology and in Clinical Epidemiology at Johns Hopkins, receiving a Master of Health Science degree. He then trained in Nutrition at Tufts University with Irwin Rosenberg, MD, and in Immunology with Charles Dinarello, MD. He was Chief of the Nutrition, Exercise Physiology, and Sarcopenia (NEPS) Laboratory, and Director of Human Studies at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, where he is currently Adjunct Professor of Medicine and Nutrition. Subsequently, Dr. Roubenoff became Sr. Director of Molecular Medicine at Millennium Pharmaceuticals and then Sr. Director, Immunology Research and Development, at Biogen Idec, where he led the Translational Medicine and Early Development efforts for the Immunology group. In 2009, Dr. Roubenoff was appointed Global Head of Musculoskeletal Translational Medicine at Novartis Institutes for Biomedical Research (NIBR), heading early clinical development for musculoskeletal and mobility disorders. In 2019 he was appointed Global Head of Translational Medicine Discovery & Profiling at NIBR.

Dr. Roubenoff has done pioneering work on the interactions of nutrition, exercise and hormonal and immune regulators of metabolism in aging and chronic disease, including rheumatoid arthritis, osteoarthritis, and HIV infection. He is an internationally recognized authority on sarcopenia, aging, translational medicine, and the use of biomarkers in drug development. He has published over 270 papers in the medical literature as well as writing for lay audiences. He is co-author of a New York Times Bestselling book on exercise and nutrition treatment of arthritis. Dr. Roubenoff has served on many NIH study sections, WHO committees, American Society for Nutrition Committees, Animal Care and Use and Institutional Review Committees, and as a reviewer for journals, foundations, and charities. He has won multiple awards, including membership in the Alpha Omega Alpha and Delta Omega honor societies; Fellow of the American College of Physicians and the American College of Rheumatology; the Robert H. Herman Memorial Award of the American Society for Nutrition; the American College of Rheumatology Senior Scholar Award; Tufts University Distinguished Faculty Award; Teacher of the Year at Johns Hopkins Medical School; and the Oliver Smith Award for Extraordinary Service and Caring at Tufts Medical Center.

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