Delta-sarcoglycan gene therapy halts progression of cardiac dysfunction, improves respiratory failure, and prolongs life in myopathic hamsters.

BACKGROUND: The BIO14.6 hamster provides a useful model of hereditary cardiomyopathies and muscular dystrophy. Previous δ-sarcoglycan (δSG) gene therapy (GT) studies were limited to neonatal and young adult animals and prevented the development of cardiac and skeletal muscle dysfunction. GT of a pseudophosphorylated mutant of phospholamban (S16EPLN) moderately alleviated the progression of cardiomyopathy. METHODS AND RESULTS: We treated 4-month-old BIO14.6 hamsters with established cardiac and skeletal muscle diseases intravenously with a serotype-9 adeno-associated viral vector carrying δSG alone or in combination with S16EPLN. Before treatment at age 14 weeks, the left ventricular fractional shortening by echocardiography was 31.3% versus 45.8% in normal hamsters. In a randomized trial, GT halted progression of left ventricular dilation and left ventricular dysfunction. Also, respiratory function improved. Addition of S16EPLN had no significant additional effects. δSG-GT prevented severe degeneration of the transverse tubular system in cardiomyocytes (electron tomography) and restored distribution of dystrophin and caveolin-3. All placebo-treated hamsters, except animals removed for the hemodynamic study, died with heart failure between 34 and 67 weeks of age. In the GT group, signs of cardiac and respiratory failure did not develop, and animals lived for 92 weeks or longer, an age comparable to that reported in normal hamsters. CONCLUSION: GT was highly effective in BIO14.6 hamsters even when given in late-stage disease, a finding that may carry implications for the future treatment of hereditary cardiac and muscle diseases in humans.

Noninvasive monitoring of gene correction in dystrophic muscle.

Gene and stem cell transfer have shown tremendous potential in rescuing dystrophic muscle in animal models. However, monitoring of gene transfer efficacy in clinical settings currently requires invasive muscle biopsies. We determined whether (1)H-magnetic resonance spectroscopy (MRS) and imaging (MRI) could be used to noninvasively monitor gene correction in dystrophic skeletal muscle. MRI/MRS measurements were performed in murine models of Limb Girdle (gammasg(-/-)) and Duchenne muscular dystrophy (mdx). Viral delivery of gammasg into gammasg(-/-) muscles was achieved using both an adenovirus and an adenoassociated virus. T(2)-weighted MRIs consistently revealed hyperintense regions in muscles of dystrophic mice, which agreed well with histologically determined damaged muscle fibers. (1)H-MRS revealed that the increase in T(2) in dystrophic muscle is not due to fatty tissue infiltration. Reintroduction of the gammasg gene in gammasg(-/-) muscles restored normal muscle histology, membrane stability, and T(2) contrast. Expression of gammasg also significantly decreased the number of pixels with increased T(2) values and MRI contrast agent uptake. Our data demonstrate that therapeutic correction of dystrophic lesions can be noninvasively monitored using endogenous MR contrast. This may be particularly relevant for future interventions in children with muscular dystrophy.