Abstract 1455: Heart Specific Mini-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy Yields an Incomplete Rescue of Cardiomyopathy
Duchenne muscular dystrophy (DMD) is a fatal genetic disease with no effective treatment. While heart failure is a leading cause of death in DMD, gene and cell therapies have largely focused on skeletal muscle therapies. The most promising skeletal muscle gene therapy treatments involve truncated mini-dystrophin genes delivered with adeno-associated viral vectors (AAV). It is currently unclear whether these mini-dystrophin genes developed for skeletal muscle can ameliorate cardiomyopathy. Here we evaluated whether cardiac specific expression of mini-dystrophin can normalize heart function in mdx mice, a model for DMD. A series of transgenic mdx mice were generated to express the skeletal muscle proven mini-dystrophin gene in the heart. Heart pathology and function were examined in adult and very old mice. Mini-dystrophin enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. ECG analysis showed PR interval normalization but heart rate and QRS duration were not corrected. Closed-chest hemodynamic assay in 22-m-old mice showed normal systolic function and ejection fraction. Heart specific mini-dystrophin therapy also improved the dobutamine stress response and survival. Surprisingly, only moderate improvement was seen in diastolic function, stroke volume and cardiac output. Heart-restricted mini-dystrophin expression also enhanced treadmill performance. Interestingly, over-expressing the mini-dystrophin gene in the normal heart profoundly displaced endogenous dystrophin yet heart function was not compromised. We demonstrate that the skeletal muscle proven mini-dystrophin gene can correct cardiac histopathology but cannot normalize heart function. These results suggest that the requirements for heart therapy could be different from those for skeletal muscle therapy. Furthermore, these findings highlight the potential importance of skeletal muscle disease in modulating heart function. Novel therapeutic strategies have to be developed to treat DMD cardiomyopathy.