Development of a Novel Universal Anti-Fibrotic Therapy

Tumor necrosis factor-related apoptosis reducing ligand (TRAIL) has been extensively studied in oncology.  TRAIL selectively induces apoptosis in cancer cells by binding to its death receptors while sparing normal cells.  However, the inherent short half-life and TRAIL resistance in primary cancers hampers its clinical development.  We have developed a stable yet potent, bioengineered TRAIL and demonstrated its extended half-life in non-human primates.  We recently discovered that systemically administered bioengineered TRAIL ameliorates fibrosis in complementary animal models with liver cirrhosis (the advanced stage of fibrosis) and pancreatic fibrosis (chronic pancreatitis) by selectively depleting activated myofibroblasts-like cells, the source cells that ultimately facilitate fibrogenesis and collagen deposition.  Fibrosis is a debilitating chronic disease caused by hardening of connective tissues with no standard of care.  In this talk, I will introduce how our research experience, at the crossroads of bioconjugation, drug delivery, and biology, enabled the engineering of stable TRAIL-based therapies, the discovery of clinically viable targets for fibrosis therapy towards clinical translation.