title: Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters.
abstract: The hereditary form comprises approximately 1/5 of patients with dilated cardiomyopathy (DCM) and is a major cause of advanced heart failure. Medical and socioeconomic settings require novel treatments other than cardiac transplantation. TO-2 strain hamsters with congenital DCM show similar clinical and genetic backgrounds to human cases that have defects in the delta-sarcoglycan (delta-SG) gene. To examine the long-term in vivo supplement of normal delta-SG gene driven by cytomegalovirus promoter, we analyzed the pathophysiologic effects of the transgene expression in TO-2 hearts by using recombinant adeno-associated virus vector. The transgene preserved sarcolemmal permeability detected in situ by mutual exclusivity between cardiomyocytes taking up intravenously administered Evans blue dye and expressing the delta-SG transgene throughout life. The persistent amelioration of sarcolemmal integrity improved wall thickness and the calcification score postmortem. Furthermore, in vivo myocardial contractility and hemodynamics, measured by echocardiography and cardiac catheterization, respectively, were normalized, especially in the diastolic performance. Most importantly, the survival period of the TO-2 hamsters was prolonged after the delta-SG gene transduction, and the animals remained active, exceeding the life expectancy of animals without transduction of the responsible gene. These results provide the first evidence that somatic gene therapy is promising for human DCM treatment, if the rAAV vector can be justified for clinical use.
authors.affiliation: Pharmacy Division, Niigata University Medical Hospital, Niigata University, Niigata 951-8520, Japan.
authors.forename: Tomie
authors.initials: T
authors.lastname: Kawada
authors.forename: Mikio
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Sakura
authors.initials: S
authors.lastname: Nakauchi
authors.forename: Ken
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Shimamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Urabe
authors.forename: Jumi
authors.initials: J
authors.lastname: Nakata
authors.forename: Chieko
authors.initials: C
authors.lastname: Hemmi
authors.forename: Fujiko
authors.initials: F
authors.lastname: Masui
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: John
authors.initials: J
authors.lastname: Monahan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Tomoh
authors.initials: T
authors.lastname: Masaki
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Toyo-Oka
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006439:Hemodynamics; D006801:Humans; D007763:Lac Operon; D008017:Life Expectancy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009200:Myocardial Contraction; D011379:Prognosis; D049031:Sarcoglycans; D012508:Sarcolemma / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D049031:Sarcoglycans