Morphological and physiological restorations of hereditary form of dilated cardiomyopathy by somatic gene therapy.
TO-2 strain hamsters with dilated cardiomyopathy, gene deletion of delta-sarcoglycan (SG) and no expression of alpha-, beta-, gamma-, and delta-SG proteins are useful for developing the potential gene therapy of intractable heart failure. We prepared recombinant adeno-associated virus vector including normal delta-SG gene driven by CMV promoter and intramurally administered in vivo. The transfected myocardium induced robust expression of both transcript and transgene for 2/3 period of the animal's life expectancy. Immunostaining demonstrated reexpression of not only delta-SG but also other three SGs in 40% cells in the transfected region and normalization of the diameter of transduced cardiomyocytes. Hemodynamic study revealed preferential amelioration of the diastolic indices (LVEDP, the dP/dt(min) and CVP). These results provide the first evidence that supplementation of a specific gene with efficient and sustained transfection capability restores the genetic, morphological, and functional deteriorations.
Kawada
T
T
Pharmacy Division, Niigata University, Japan.
Sakamoto
A
A
Nakazawa
M
M
Urabe
M
M
Masuda
F
F
Hemmi
C
C
Wang
Y
Y
Shin
W S
WS
Nakatsuru
Y
Y
Sato
H
H
Ozawa
K
K
Toyo-oka
T
T
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D048429:Cell Size / Q000187:drug effects; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000008:administration & dosage* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007267:Injections / Q000379:methods; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D049031:Sarcoglycans; D014162:Transfection; D016896:Treatment Outcome; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049031:Sarcoglycans; D001616:beta-Galactosidase