Systemic Transplantation of MyoPAXon: IND Enabling Studies for the Treatment of DMD - PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy, caused due to mutations in the dystrophin gene. DMD is characterized by progressive muscle wasting and overall loss of muscle function. DMD patients become wheel chair dependant by 12 years of age and the associated cardiorespiratory complications result in their early death around 20 years of age. Dystrophinopathies, which include DMD and the less severe phenotype Becker, are X-linked recessive disorders affecting primarily males, with 16,765 patients in the US. There is no cure for DMD and corticosteroids such as prednisone are used for symptomatic relief. Many emerging therapeutic approaches such as exon skipping, gene correction and adeno-associated virus (AAV) mediated gene therapy aim to increase dystrophin production but are restricted by the immune response, questionable efficacy, short term effect, high cost and are limited to certain mutations. Cell therapies have tremendous potential to treat degenerative conditions and genetic diseases. However, to date, production scalability, safety and efficacy of cell therapy have limited the clinical transition of cell therapies. Myogenica has developed MyoPAXon, a cGMP certified, induced pluripotent stem cell (iPSC) derived myogenic platform which regenerates skeletal muscle, leading to functional improvement. MyoPAXon not only replaces diseased muscle fibers with normal functional muscle fibers but also creates a muscle stem cell pool, enabling long-term muscle regeneration. Preclinical animal studies of intramuscular, intravascular and intra-arterial transplantation of MyoPAXon have shown significant engraftment and functional improvement. Myogenica has advanced intramuscular delivered MyoPAXon toward the clinic, with an IND expected in Q2 this year and first DMD patients to be treated later this year. As a next step, Myogenica seeks to develop systemically delivered MyoPAXon. The current STTR Fast track project, aimed at validating the efficacy and safety of systemic MyoPAXon delivery in preclinical animal models, will be carried out in collaboration with the University of Minnesota. Systemic MyoPAXon delivery will allow for the targeting of multiple skeletal muscles with a single injection, making it a compelling therapy for DMD patients and for a range of muscular dystrophies, since MyoPAXon’s mechanism is not mutation specific. During Phase I-Aim 1, we will select an optimal systemic delivery route (IV or IA) and conduct dose finding studies in immunodeficient NSG mice, assessing comparative engraftment. This will be followed by a preliminary safety assessment in Aim 2 where the presence of human cells in non-target tissues and organs of mice will be evaluated. In Phase II-Aim 1 will continue evaluating efficacy in the immune deficient, -NSGmdx4Cv mouse model for DMD, using the optimised dose and route determined in Phase I. During the Phase II-Aim 2, comprehensive GLP toxicology and pharmacokinetics will be performed on NSG mice which will be followed by safety and biodistribution evaluation in a Non-Human Primate (NHP) model. The results obtained from this STTR proposal will be leveraged in an Investigational New Drug (IND) application for clinical studies of systemic MyoPAXon.
