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.