Whole body single AAV microgene in canine DMD

University Of Missouri-Columbia, Columbia MO

Investigators

Linked publications & trials

Abstract

Project Description Duchenne muscular dystrophy (DMD) is a lethal X-linked muscle-wasting disease caused by dystrophin deficiency. Adeno-associated virus (AAV)-mediated systemic microdystrophin (μDys) gene therapy aims to treat DMD with a bodywide expression of abbreviated dystrophin. With the support from NIH, we have made many important contributions to the development of AAV μDys gene therapy. We pioneered AAV μDys therapy for DMD cardiomyopathy; we were among the first to show that AAV μDys therapy can improve muscle force in the mouse model; we were the first to demonstrate the histological and physiological benefits of AAV μDys therapy in a large dystrophic mammal (the canine DMD model) by intramuscular injection; and we were the first to achieve successful bodywide AAV μDys therapy in the canine DMD model. In addition, we discovered several domains important for μDys function, including the dystrophin nNOS-binding domain and membrane-binding domains. These studies and the outstanding contributions from many other laboratories have led to systemic AAV μDys trials in DMD patients by several biopharma companies and the recent approval of an AAV μDys drug by the FDA. Despite encouraging progress, several important issues surfaced in clinical trials. These include toxicity associated with high-dose systemic AAV delivery, low efficacy and immunogenicity of current μDys constructs, and uncertainty of the longevity of the therapy. The field is also hindered by the lack of a good method for predicting AAV performance in human muscle. The canine model is the most established large animal model. It faithfully recapitulates human disease. We are a world-leading laboratory developing DMD gene therapy in the canine model. We recently developed a xenograft model for testing systemic AAV delivery in human muscle. In this renewal, we will leverage our expertise in AAV μDys therapy, the canine DMD model, and the human muscle xenograft model to (1) address whether the toxicity associated with the high-dose AAV administration can be attenuated with the newly developed more potent myotropic AAV capsids; (2) determine whether myotropic AAV μDys therapy can result in long-term therapeutic benefits in the canine DMD model; (3) identify the best-performing AAV capsids for systemic gene therapy in human muscle, and (4) develop more potent, deimmunized next-generation μDys constructs. Our studies will greatly advance AAV μDys gene therapy for DMD and reduce the disease burden on patients, families, and society.