Prevention of cardiomyopathy in -sarcoglycan knockout mice after systemic transfer of targeted adeno-associated viral vectors
Open Access
- 13 February 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 82 (3), 404-410
- https://doi.org/10.1093/cvr/cvp061
Abstract
δ-Sarcoglycan is a member of the dystrophin-associated glycoprotein complex linking the cytoskeleton to the extracellular matrix. Similar to patients with defects in the gene encoding δ-sarcoglycan (Sgcd), knockout mice develop cardiomyopathy and muscular dystrophy. The aim of our study was to develop an approach for preventing cardiomyopathy in Sgcd-deficient mice by cardiac expression of the intact cDNA upon systemic delivery of adeno-associated viral (AAV) vectors. We packaged the Sgcd cDNA under transcriptional control of a myosin light chain-promoter fused with a cytomegalovirus enhancer into AAV-9 capsids. Vectors carrying either the Sgcd cDNA or an enhanced green fluorescent protein (EGFP) reporter gene were intravenously injected into adult Sgcd knockout mice. After 6 months, immunohistochemistry revealed almost complete reconstitution of the sarcoglycan subcomplex in heart but not skeletal muscle of mice with the Sgcd vector. Furthermore, Sgcd gene transfer resulted in prevention of cardiac fibrosis and significantly increased running distance measured by voluntary wheel running. Left ventricular function remained stable in mice expressing Sgcd while it deteriorated in EGFP controls within 6 months, paralleled by increased expression of brain natriuretic peptide, a molecular marker of heart failure. Our study establishes an approach to specifically treat hereditary cardiomyopathies by targeting gene expression into the myocardium upon systemic application of AAV vectors.Keywords
This publication has 38 references indexed in Scilit:
- Genetic Disruption of Calcineurin Improves Skeletal Muscle Pathology and Cardiac Disease in a Mouse Model of Limb-Girdle Muscular DystrophyOnline Journal of Public Health Informatics, 2007
- Phenotypic Correction of α-Sarcoglycan Deficiency by Intra-arterial Injection of a Muscle-specific Serotype 1 rAAV VectorMolecular Therapy, 2007
- Efficacy and safety of adeno‐associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapyJournal of Thrombosis and Haemostasis, 2006
- Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8Molecular Therapy, 2006
- Age-Dependent Effect of Myostatin Blockade on Disease Severity in a Murine Model of Limb-Girdle Muscular DystrophyThe American Journal of Pathology, 2006
- Sustained Whole-Body Functional Rescue in Congestive Heart Failure and Muscular Dystrophy Hamsters by Systemic Gene TransferCirculation, 2005
- Efficient and long-term intracardiac gene transfer in δ-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectorsGene Therapy, 2003
- Delivery ofα- andβ-Sarcoglycan by Recombinant Adeno-Associated Virus: Efficient Rescue of Muscle, but Differential ToxicityHuman Gene Therapy, 2002
- Evaluation of cardiac and respiratory involvement in sarcoglycanopathiesNeuromuscular Disorders, 2001
- Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrixNature, 1992