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, and results in severe functional disability 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. Gene editing and replacement therapies are being developed but face significant hurdles concerning efficacy and safety. We propose to develop Advertent Biotherapeutics' proprietary agent ADA011, a specific TGF-β1/3 inhibitor, into a therapy that inhibits muscle FD and preserves muscle function in LGMD2B patients. We hypothesize that this could help delay the onset of symptoms, ameliorate pathologies, and slow disease progression. Moreover, ADA011 could be used alone or in combination with emerging gene therapies to prevent progression of existing FD in patients. We have identified ADA011 as a potent, well-tolerated TGF-β1/3 inhibitor with efficacy inhibiting adipogenic differentiation an in vitro model and inhibiting muscle FD in an in vivo mouse model of induced muscle injury. We propose to use ADA011 to inhibit muscle FD in a mouse model of LGMD2B (dysferlin-null). In Aim 1 we will test this hypothesis by analyzing disease progression over 20 weeks in dysferlin-null mice treated with ADA011 compared to vehicle control. In Aim 2 we will determine whether muscle healing and function are improved by ADA011 treatment after acute injury in dysferlin-null mice. Efficacy of ADA011 in this mouse model of LGMD2B would powerfully validate the therapeutic potential of ADA011 and support development of ADA011 as a novel therapy for LGMD2B patients. Since therapeutics that inhibit FD of muscles in LGMB2B patients do not exist, ADA011 would be a first-in-class therapeutic that could significantly improve and extend health and lifespan of LGMD2B patients.