Project One: Potential Therapies for the Muscular Dystrophies

Project Lead: H. Lee Sweeney, PhD, University of Florida

Project Co-Lead: David Hammers PhD, University of Florida

The multifaceted pathologies associated with muscular dystrophies, particularly Duchenne muscular dystrophy (DMD), represent major challenges to the development and clinical implementation of effective therapeutics for these diseases. AAV gene therapy, delivering a µdystrophin construct to all striated muscles, is now poised to bring about transformative alterations in DMD disease course. However, a number of significant hurdles remain before it can be successfully applied to all DMD patients. There is a need to prevent and resolve fibrosis in order to improve the efficiency of delivery and enable the use of lower viral doses. Additional therapeutics may be needed to slow the skeletal muscle disease progression that remains after µdystrophin therapy. Perhaps the most critical issue facing AAV gene therapy for DMD is that current µdystrophin designs and vector doses are optimized for skeletal muscle without sufficient evaluation of the potential impact on cardiac muscle function. The aims of this project are motivated by our observations in the D2.mdx model of DMD: (1) µdystrophin overexpression is highly beneficial for skeletal muscle, but it does not completely prevent progressive fibrosis, especially in the diaphragm; (2) AAV delivery is markedly less efficient in highly fibrotic muscle; (3) µdystrophin fails to rescue the heart; and (4) countermeasures can compensate for deficiencies of the µdystrophins, and may form the basis of combination therapies for DMD.