title: Prevention of cardiomyopathy in delta-sarcoglycan knockout mice after systemic transfer of targeted adeno-associated viral vectors.
abstract: OBJECTIVE
  Delta-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 delta-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our study establishes an approach to specifically treat hereditary cardiomyopathies by targeting gene expression into the myocardium upon systemic application of AAV vectors.
authors.affiliation: Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Goehringer
authors.forename: Désirée
authors.initials: D
authors.lastname: Rutschow
authors.forename: Ralf
authors.initials: R
authors.lastname: Bauer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schinkel
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Kleinschmidt
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000517:prevention & control*; D000229:Dependovirus; D005080:Exercise Test; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006333:Heart Failure / Q000517:prevention & control; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D049031:Sarcoglycans / Q000235:genetics* / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D049031:Sarcoglycans