"CURE-DMD": Development of Next-Generation Gene Therapy for Duchenne Muscular Dystrophy (FWOAL839)

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the gene dystrophin, which results in progressive weakness and wasting of the heart and skeletal muscles causing loss of mobility in early childhood and death in young adults due to cardiopulmonary failure. Over the years, pharmacological and/or surgical interventions are useful to alleviate cardiac symptoms in DMD patients, however these modalities do not provide a cure in the disease. Nonetheless, recent advances in adeno-associated virus (AAV)-mediated gene therapy have provided unprecedented opportunities to treat DMD. Unfortunately, challenges remain in achieving safe, robust and widespread expression of the dystrophin gene in the heart and skeletal muscles. Moreover, few studies focus on the amelioration of the cardiac dysfunction. It is therefore imperative to further improve the efficacy and safety of tissue-directed gene therapy applications for DMD, ideally by developing more robust viral vectors that allow for in vivo sustainable and widespread therapeutic gene expression at safer vector doses. This project will focus on the development and in vivo validation of novel "next-generation" AAV vectors containing the most potent heart/muscle-specific cis-regulatory modules (CRM) and therapeutic genes for effective histopathologic and functional correction, in order to achieve simultaneous and robust amelioration of the heart and skeletal muscle dysfunctions in a clinically-relevant DMD mouse model.

Keywords:Duchenne Muscular Dystrophy

Disciplines:Animal morphology, anatomy and physiology