A novel agent for preventing fatty degeneration of muscles in LGMD2B

Abstract Muscular dystrophies are grave genetic disorders characterized by muscle wasting and progressive loss of muscle function. Approximately 250,000 individuals are currently affected by some form of MD in the US. Although MDs are caused by mutations in different genes, the muscle pathologies patients develop are shared and manifest as muscle fatty degeneration (FD) through replacement of necrotic muscle fibers by adipose and fibrotic tissue leading to loss of muscle function. Limb Girdle Muscular Dystrophy 2B (LGMD2B) affects shoulder and hip muscles first, and results in severe disability and loss of ambulation by a patient’s second or third decade. There is currently no cure or therapy for LGMD2B since glucocorticoids, which are the standard-of-care for some types of MD, are not advised for LGMD2B. We propose to develop Advertent Biotherapeutic’s proprietary agent ADA011, a specific TGF-β1/3 inhibitor, into a therapy that inhibits muscle FD and preserves muscle function in LGMD2B patients. We identified ADA011 as a potent inhibitor of de novo adipogenesis in vitro and have now demonstrated that ADA011 inhibits muscle FD and disease progression in a mouse model of LGMD2B (i.e., Bla/J mice). In addition, we showed that ADA011 has favorable pharmacokinetics and is safe in mice. In this Phase 2 proposal we will demonstrate long-term efficacy of ADA011 in Bla/J mice and demonstrate safety in an IND-enabling study GLP toxicity study in rats.