Preclinical validation of AVGN7 for treating obesity and type 2 diabetes mellitus.

PROJECT SUMMARY. Obesity is the most challenging non-infectious health care issue of our time. Since 1980, its prevalence has increased dramatically and as a result, so has the prevalence of many associated disorders including type 2 diabetes mellitus (T2DM). These diseases together cost the healthcare industry more than any other disease and despite notable advances in drug development, the burden of care is expected to continue rising. Thus, novel approaches capable of significantly reducing adiposity and restoring insulin sensi- tivity could revolutionize the treatment of obesity and T2DM while substantially reducing healthcare costs. Our objective is to validate the use of AVGN7 (rAAV6:SMAD7), a gene therapeutic for enhancing skeletal muscle mass and function, for treating obesity/T2DM. We hypothesize that AVGN7 will significantly enhance lean body mass while decreasing fat mass and restoring insulin sensitivity. This is based on high profile preclinical studies demonstrating AVGN7 to attenuate myostatin/ActRIIb signaling and, thereby, increasing muscle protein synthe- sis, muscle mass, muscle strength as well as exercise and cardiac capacity. Attenuating this pathway with genetic models is well known to prevent de novo synthesis of triglycerides and to improve insulin sensitivity. Myostatin/ActRIIb pharmacological inhibitors have similar effects, although to date some have produced serious off-target effects compromising their development while the projected treatment costs prohibit others from being used to treat a chronic condition like obesity/T2DM. By contrast, AVGN7 was specifically designed to avoid these off-target effects, to have superior activity and to be a long-term solution for chronic conditions. Our mile- stones are to validate the use of AVGN7 in (i) restoring lean body mass and insulin sensitivity in obese mice fed a high fat diet and (ii) preventing development of obesity/T2DM in long-term studies. The proposed approach is truly innovative as it utilizes a novel muscle-specific gene therapeutic to combat obesity/T2DM. In essence, it fights fat with muscle. These studies are also highly significant as they will provide proof-of-concept data to be used in a future IND filing that in turn, will help advance AVGN7 towards clinical trials with extremely obese subjects, those with the highest risk for developing T2DM and other serious complications.