Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters.
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.
Toyo-oka
Teruhiko
T
Department of Organ Pathophysiology and Internal Medicine, University of Tokyo, Tokyo, Japan. toyoka-2im@h.u-tokyo.ac.jp
Kawada
Tomie
T
Xi
Hang
H
Nakazawa
Mikio
M
Masui
Fujiko
F
Hemmi
Chieko
C
Nakata
Jumi
J
Tezuka
Asaki
A
Iwasawa
Kuniaki
K
Urabe
Masashi
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Monahan
John
J
Ozawa
Keiya
K