Abstract 2098: Restoration of Sarcoglycan Complex Halted Disease Progression in BIO14.6 Hamsters With Established Heart Failure
BIO14.6 hamster with the absence of delta-sarcoglycan (dSG) develops progressive heart failure and is a model of human inherited cardiomyopathy. It also represents human limb-girdle muscular dystrophy (LGMD) type 2F. Previous gene therapies have treated neonatal or juvenile BIO14.6s, primarily to test preventive effects. Here, we assessed the therapeutic effects of systemic dSG delivery in BIO14.6s with established heart failure. We delivered a recombinant adeno-associate virus serotype 9 (rAAV9) vector carrying human dSG gene to 16 weeks old BIO14.6s with significantly reduced left ventricular (LV) functions (by echocardiography, fractional shortening: 31.3±4.89, n=30, vs. normal hamsters, 45.8±1.71, n=6, mean±SEM, P<0.001). The animals were randomly assigned into 3 groups (ten BIO14.6s per group): saline-treatment, rAAV9/dSG-treatment, and rAAV9/dSG-treatment supplemented with an AAV9 carrying a pseudo-phosphorylated mutant of phospholamban (S16EPLN) - a sarcoplasmic reticulum Ca2+ uptake enhancer. Echocardiography revealed that the dSG treatment nearly completely halted the progression of LV dysfunction over 65 weeks, while the S16EPLN supplement slightly and transiently enhanced the dSG effects. Hemodynamic measurements confirmed an increase in the maximum first derivative of LV pressure, an index of LV systolic function, by ~45% at 25 weeks of the treatment. While the medial survival of control BIO14.6s was 60 weeks, the first loss of dSG-treated BIO14.6s was at the age of 93 weeks. Immunofluorescence staining confirmed that sarcoglycan complex was completely reconstituted on the sarcolemma including transverse tubules by the dSG treatment. Three-dimensional electron microscopy revealed that the therapy entirely removed the microstructural degeneration of transverse tubules. It also restored caveolin-3 and dysferlin on the transverse tubule membranes. The genetic mutations of these genes are associated with LGMDs. In conclusion, a systemic gene therapy using rAAV vectors is a safe and effective strategy to rebuild sarcolemmal protein complexes, to restore the structure of membrane organelles, and to treat inherited cardiomyopathy and heart failure in the highly affected myocardium.