title: 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 delta-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 beta-antagonist both in humans and in TO-2 hamsters.
  
  
  METHODS
  Gene therapy for DCM was achieved by supplementing the delta-SG gene with rAAV vector and intramurally delivering rAAV-delta-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 delta-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 delta-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.
authors.affiliation: Department of Organ Pathophysiology and Internal Medicine, University of Tokyo, Tokyo, Japan. toyoka-2im@h.u-tokyo.ac.jp
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Toyo-oka
authors.forename: Tomie
authors.initials: T
authors.lastname: Kawada
authors.forename: Hang
authors.initials: H
authors.lastname: Xi
authors.forename: Mikio
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Fujiko
authors.initials: F
authors.lastname: Masui
authors.forename: Chieko
authors.initials: C
authors.lastname: Hemmi
authors.forename: Jumi
authors.initials: J
authors.lastname: Nakata
authors.forename: Asaki
authors.initials: A
authors.lastname: Tezuka
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Iwasawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Urabe
authors.forename: John
authors.initials: J
authors.lastname: Monahan
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa