Gene therapy for mitochondrial disease by delivering restriction endonucleaseSmaI into mitochondria

Journal of Biomedical Science - Tập 9 - Trang 534-541 - 2002
Masashi Tanaka1,2, Harm-Jan Borgeld1,2, Jin Zhang1,2, Shin-ichi Muramatsu3, Jian-Sheng Gong1,2, Makoto Yoneda4, Wakako Maruyama5, Makoto Naoi2, Tohru Ibi6, Ko Sahashi6, Masayo Shamoto5, Noriyuki Fuku1,7, Miyuki Kurata1, Yoshiji Yamada1,2, Kumi Nishizawa1, Yukihiro Akao1,2, Nobuko Ohishi2, Shigeaki Miyabayashi8, Hiraku Umemoto9, Tatsuo Muramatsu9, Koichi Furukawa10, Akihiko Kikuchi11, Imaharu Nakano3, Keiya Ozawa12, Kunio Yagi1,2
1Department of Gene Therapy, Gifu International Institute of Biotechnology, Mitake, Gifu, Japan
2Institute of Applied Biochemistry, Mitake
3Department of Neurology, Jichi Medical School, Tochigi
4Second Department of Internal Medicine, Fukui Medical University, Fukui
5Laboratory of Biochemistry and Metabolism, Department of Basic Gerontology, National Institute for Longevity Sciences, Obu
6Neurology Section, Department of Internal Medicine, Aichi Medical University, Aichi
7Japan Science and Technology Corporation, Tokyo
8Department of Pediatrics, Sendai National Hospital, Sendai
9Department of Applied Genetics and Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya
10Department of Biochemistry,Graduate School of Medical Sciences, Nagoya University, Japan
11Department of Medical Mycology, Graduate School of Medical Sciences, Nagoya University, Nagoya
12Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

Tóm tắt

The restriction endonucleaseSmaI has been used for the diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa disease or Leigh's disease, caused by the Mt8993T→G mutation which results in a Leu156Arg replacement that blocks proton translocation activity of subunit a of F0F1-ATPase. Our ultimate goal is to applySmaI to gene therapy for this disease, because the mutant mitochondrial DNA (mtDNA) coexists with the wild-type mtDNA (heteroplasmy), and because only the mutant mtDNA, but not the wild-type mtDNA, is selectively restricted by the enzyme. For this purpose, we transiently expressed theSmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by theSmaI enzyme showed specific elimination of the mutant mtDNA. This elimination was followed with repopulation by the wild-type mtDNA, resulting in restoration of both the normal intracellular ATP level and normal mitochondrial membrane potential. Furthermore, in vivo electroporation of the plasmids expressing mitochondrion-targetedEcoRI induced a decrease in cytochromec oxidase activity in hamster skeletal muscles while causing no degenerative changes in nuclei. Delivery of restriction enzymes into mitochondria is a novel strategy for gene therapy of a special form of mitochondrial diseases.

Tài liệu tham khảo

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Journal of Biomedical Science

Tập 9

534-541

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