Abstract 3808: AAV-9 Micro-Dystrophin Gene Therapy Halts Heart Disease Progression in Symptomatic Dystrophic Mice
Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by mutations in the dystrophin gene. Lack of dystrophin causes muscle wasting that eventually leads to premature death from respiratory and/or heart failure. Heart disease can be detected as early as six years of age in DMD patients. As heart disease progresses, patients begin to show overt signs of severe dilated cardiomyopathy and up to 40% of patients die from heart disease. Adeno-associated virus (AAV) mediated micro-dystrophin gene therapy brings the hope of ameliorating DMD. Dystrophin-deficient mdx mice exhibit a cardiac phenotype similar to human DMD patients albeit at a delayed progression (Bostick et al 2008 Cir Res102:121–130). Delineating the potential of gene therapy at different stages of dystrophic cardiomyopathy is critical to developing a successful gene therapy strategy. Investigators, including ourselves, have previously shown that AAV-9 can efficiently transduce the adult mouse heart. In this study, we delivered an AAV-9 micro-dystrophin vector to mdx mice at both the pre-clinical and symptomatic stages of disease (1–5 x 1012 viral particles per mouse). Micro-dystrophin expression and cardiac function were analyzed six weeks to four months post gene transfer. Immunofluorescence staining revealed widespread micro-dystrophin expression in the heart. ECG analysis of mice treated during the pre-clinical stage showed normalization of heart rate, PR interval and QT interval. The cardiomyopathy index was also improved. Mice treated during the later stages of disease showed an incomplete improvement. Notably, ECG analysis showed an improvement in the QRS duration in treated mice (AAV treated, 7.10 ± 0.25 ms; untreated control, 9.36 ± 0.14 ms; p < 0.05). Mice in the later stages of disease also showed a significant increase in the maximal rate of pressure development (dP/dt max) during left ventricular catheterization assay (AAV treated, 11,810 ± 1,225 mmHg/sec; untreated control, 4,864 ± 1,099 mmHg/sec; p < 0.05). In summary, our results suggest that AAV-9 mediated micro-dystrophin gene therapy is a promising approach to treat DMD heart disease. However, the extent of dystrophic cardiomyopathy when gene therapy is initiated may be a critical modifier of disease rescue.