"CURE-DMD": Development of Next-Generation Gene Therapy for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene resulting in progressive weakness and wasting of the heart and skeletal muscle. This causes loss of mobility in early childhood and death in young adults due to cardiopulmonary failure. Current pharmacological and/or surgical interventions may alleviate some cardiac symptoms, these treatments are not curative.

Nonetheless, recent advances in adeno-associated virus (AAV)-mediated gene therapy provide new opportunities to treat DMD. Nevertheless, achieving safe, robust and widespread dystrophin expression in the heart and skeletal muscles remains challenging. Moreover, few studies focus on the amelioration of the cardiac dysfunction. It is therefore imperative to further improve the efficacy and safety of heart and skeletal muscle--directed gene therapy for DMD. More robust AAV vectors will therefore be developed that allow for sustainable and widespread therapeutic gene expression. This project focuses on the development and in vivo validation of novel "next-generation" AAV-based myospecific vectors that display engineered capsids capable of efficient myospecific delivery in the afflicted target tissues, in conjunction with the use of novel potent heart/muscle-specific cis-regulatory modules (CRM) that boost expression of the therapeutic gene. The ultimate goal is to simultaneously achieve robust amelioration of heart and skeletal muscle dysfunction in a clinically-relevant DMD mouse model.