Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 2, 901-906, January 22, 2002
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
Tomie Kawada*, Mikio Nakazawa, Sakura Nakauchi, Ken Yamazaki, Ryoichi Shimamoto, Masashi Urabe§, Jumi Nakata, Chieko Hemmi, Fujiko Masui, Toshiaki Nakajima, Jun-Ichi Suzuki, John Monahan¶, Hiroshi Sato*, Tomoh Masaki, Keiya Ozawa§, and Teruhiko Toyo-oka,**
Department of Organ Pathophysiology and Internal Medicine, Cardiovascular Medicine, University of Tokyo, Tokyo 113-0033, Japan; * Pharmacy Division, Niigata University Medical Hospital, and Department of Medical Technology, School of Health Sciences, Niigata University, Niigata 951-8520, Japan; § Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan; Research Institute, National Cardiovascular Institute, Suita 565-8565, Japan; and ¶ Avigen, Inc., Alameda, CA 94502
The hereditary form comprises 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 -sarcoglycan (-SG) gene. To examine the long-term in vivo supplement of normal -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 -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 -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.
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www.pnas.org/cgi/doi/10.1073/pnas.022641799 |
