Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters

Abstract

Background: The TO-2 hamster is an animal model of dilated cardiomyopathy (DCM). It has genetic and clinical features in common with humans who carry the gene deletion or mutation of the δ-sarcoglycan (SG) gene, a component in dystrophin-related proteins (DRP). DRP stabilise the sarcolemma during cardiac contraction. We performed in vivo gene therapy of the TO-2 hamster, whose heart is defective in all four SG proteins, to determine its potential as a model for therapy for DCM. In addition to the hereditary origin, heart failure is aggravated by treatment with catecholamines and ameliorated by the administration of some kinds of β-antagonist both in humans and in TO-2 hamsters. Methods: Gene therapy for DCM was achieved by supplementing the δ-SG gene with rAAV vector and intramurally delivering rAAV-δ-SG into the cardiac apex and left ventricle. Results: This treatment resulted in: (i) a sustained and non-pathogenic expression of both the transcript and transgene of δ-SG and all other SG proteins; (ii) improvement to both morphological and physiological deterioration; and (iii) rescued prognosis compared with untreated TO-2 hamsters, and TO-2 hamsters transfected with reporter gene alone. Another acute heart-failure model was prepared by high-dose isoproterenol treatment in Wistar rats, which resulted in: (i) translocation of dystrophin, but not δ-SG, from the cardiac sarcolemma to the myoplasm; and (ii) fragmentation of dystrophin, probably due to the activation of endogenous protease(s) or proteasome(s) that contributed to muscular dystrophy-like degeneration occurring specifically in cardiomyocytes. Conclusions: Both the TO-2 hamster and the isoproterenol-treated Wistar rat models commonly experience disruption of dystrophin or DRP. Targeting the responsible gene with the use of a potent vector may provide a novel strategy for the treatment of advanced heart failure.