LSI Seminar Series: Ariel Feldstein, M.D., Novo Nordisk and University of California San Diego
Inflammasome Modulation to Treat Fibrotic Diseases
Cell death and inflammation are two central elements in the development of liver fibrosis and injury. Inflammasomes are intracellular multiprotein complexes expressed in both hepatocytes and non-parenchymal cells in the liver that are key regulators of inflammation and cell fate. They respond to cellular danger signals by activating caspase 1, releasing the proinflammatory cytokines IL-1β and IL-18, as well as initiating a novel pathway of programmed cell death termed “pyroptosis.” This novel type of cell death is intrinsically pro-inflammatory because it is associated with the release of IL-1β and other intracellular content to the extracellular space including NLRP3 inflammasome particles that represent a novel mechanism to spread inflammasome signaling to adjacent cells. These downstream effectors of NLRP3 inlfammasome activation in the liver can initiate and perpetuate abnormal wound-healing responses with the principle cellular target being the activation of hepatic stellate cells. From the various inflammasomes, the NLRP3 inflammasome has been increasingly implicated in the pathogenesis of chronic inflammatory liver diseases, including nonalcoholic steatohepatitis, a disease process that is soaring and has evolved as a primary cause of liver fibrosis and need for liver transplantation. In this seminar, I will highlight the growing evidence for both indirect and direct effects of NRLP3 inflammasome activation in triggering liver fibrosis and its role for therapeutic intervention for treatment of Nonalcoholic Steatohepatitis (NASH).
Ariel Feldstein leads research and early development in the liver and kidney disease therapeutic areas at Novo Nordisk.
Ariel is a physician-scientist with more than 20 years of experience in academic-industry translational research in metabolic and liver diseases, supported continuously for the last 18 years by the National Institutes of Health (NIH), as well as several non-federal grants including the American Gastroenterological Association (AGA), The American Association for Liver Diseases (AASLD), and the American College of Gastroenterology (ACG). Ariel trained in pediatrics and liver diseases as well as translational research at the Mayo Clinic in Rochester, Minnesota and was then recruited to the Cleveland Clinic where he went on to become the Director of Research for the Pediatric Institute. In 2011, he moved to San Diego as Chief of the Department of Gastroenterology, Hepatology and Nutrition at Rady Children’s Hospital and Tenured Professor of Pediatrics and Liver diseases at the University of California San Diego (UCSD). In 2021, Ariel transitioned to the pharma industry, working first as a Senior Scientific Advisor and in 2022 assumed the role of Corporate Vice President for Liver and Kidney disease research in R&ED at Novo Nordisk. In this position he is responsible for discovery research and preclinical development driving novel targets in chronic liver diseases including non-alcoholic steatohepatitis (NASH) and chronic kidney diseases towards clinical development. He is additionally responsible to lead external high-profile collaborations with both biotech and academic institutions including the Flagship/ Pioneering Medicine – Novo Nordisk collaboration as well as collaborations with MIT, BROAD Institute, and Harvard.
Ariel is an elected member of the American Society of Clinical Investigation. He has published over 200 peer-reviewed publications in top medical journals. His research laboratory has provided important evidence on the role of cell death pathways, and inflammatory responses driven by Inflammasomes during chronic injury, and fibrosis. He is an innovator with several issued patents including the development of soluble cytokeratin-18 as a diagnostic biomarker for NASH. He is a serial entrepreneur being the founder of three Biotech Companies, Torrey Pines Metabolic Health Labs, Jecure Therapeutics (acquired by Roche in 2018), and Elgia Therapeutics.