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

https://doi.org/10.1046/j.1444-2892.2002.00151.xGet rights and content

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.

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      The sarcoglycan null mice and the delta sarcoglycan-deficient cardiomyopathic hamsters (BIO14.6, BIO53.58, CHF147, TO-2) are also well-established animal models for sarcoglycan-deficient cardiomyopathy. The spectrum of therapeutic approaches that has been used to treat the dilated cardiomyopathy in the hamster models is very broad and reaches from classical pharmacotherapy approaches58,59 to gene replacement therapy,60–62 cellular therapies,63–65 and recombinant growth factor therapies.66–69 Despite numerous treatment studies in the cardiomyopathic hamster models over the past 40 years, many of which have been shown to be effective, no controlled trial to treat cardiomyopathy in patients with LGMD2C-F has been conducted so far.

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    Presented at the International Society for Heart Research and International Union of Physiological Societies World Congress Satellite Meeting, Models of Cardiovascular Disease, 2–4 September 2001, Brisbane, Australia.

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