Gene therapy of Parkinson’s disease using Adeno-Associated Virus (AAV) vectors

Ozawa, Keiya; Fan, Dongsheng; Shen, Yan‐Qin; Muramatsu, Shin‐ichi; Fujimoto, Ken’ichi; Ikeguchi, Kunihiko; Ogawa, Matsuo; Urabe, Masashi; Kume, Akihiro; Nakano, Imaharu

doi:10.1007/978-3-7091-6284-2_15

Cited by 15 publications

(15 citation statements)

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“…Delivery of genes encoding dopamine-synthesizing enzymes by use of AAV vectors has been successfully applied in a primate model of Parkinson's disease [14,17]. AAV vectors are expected to be useful for eliminating mutant mtDNA from the central nervous system as well as from cardiac and skeletal muscles.…”

Section: Discussionmentioning

confidence: 99%

Gene Therapy for Mitochondrial Disease by Delivering Restriction Endonuclease <i>Sma</i>I into Mitochondria

et al. 2002

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The restriction endonuclease SmaI 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 apply SmaI 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 the SmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by the SmaI 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-targeted EcoRI induced a decrease in cytochrome c 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.

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Section: Discussionmentioning

confidence: 99%

Gene Therapy for Mitochondrial Disease by Delivering Restriction Endonuclease <i>Sma</i>I into Mitochondria

et al. 2002

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“…The AAV vector is by virtue of its unique characteristics, a potentially useful gene transfer vehicle for neurologic gene therapies. [15][16][17] The advantages of AAV vector include the lack of any associated disease with a wildtype virus, 18,19 possible integration of the gene into the host genome 20,21 and the ability to transduce nondividing cells. 22 By employing AAV bcl-2, we have shown that post-ischemic injection of the vector is effective for conferring neuroprotection in the gerbil hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death

et al. 2000

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The proto-oncogene bcl-2 is known as an anti-apoptotic gene that confers the ability to block neuronal cell death after transient ischemia. In order to examine whether the bcl-2 gene can be used for protection of ischemic brain injury, we generated adeno-associated virus (AAV) vectors capable of expressing human bcl-2. Replication-defective AAV vectors were found effectively to transfer and express bcl-2 gene in the gerbil hippocampal neurons. Transduction with AAV bcl-2 5 days before forebrain ischemia prevented the DNA frag-

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“…For this application, genes have thus far been packaged into viral vectors and injected into the brain with the goal of either delivering genes for DA-synthesizing enzymes to the striatum or providing neuroprotection to block or slow ongoing degenerative processes by providing genes for growth factors, antioxidant molecules, or antiapoptotic substances (Muramatsu et al, 2003). Adeno-associated virus (AAV) has been the most commonly used vector because of its ease of use and safety profile (Ozawa et al, 2000;Bankiewicz et al, 2006). This approach is currently being tested in a number of Phase I and II clinical trials (Hickey and Stacy, 2011).…”

Section: B Parkinson's Diseasementioning

confidence: 99%