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2003 Fiscal Year Final Research Report Summary

Primate Study for Gene Therapy of Porkinson's disease for clinic

Research Project

Project/Area Number 14370211
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionJuntendo University

Principal Investigator

MOCHIZUKI Hideki  Juntendo University, Dept. of Neurology, Assistant professor, 医学部, 講師 (90230044)

Project Period (FY) 2002 – 2003
KeywordsParkinson's disease / Gene therapy / AAV vector / Caspase 11 / Apaf-1-DN / MPTP
Research Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. In this report, we focused on the pathogenesis and treatment of PD.
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a parkinsonian syndrome in humans and primates after selective uptake of its metabolite, MPP^+, into dopaminergic neurons. We sought to determine the major pathway of MPTP toxicity from among several apoptotic pathways. We already established in vivo models of the inhibition of caspase cascade using adeno-asociated virus (AAV) vectors. We showed persistent high levels of focal Apaf-1 CARD or caspase-1 C285G mutant expression were available for further in vivo studies and for possible anti-apoptotic gene therapy in patients with PD. In this report, we confirm the effect and the safe of AAV vector using the primates for the clinical trial. AAV vector, a single-strand DNA virus from the parvovirus family, has become one of the most promising vectors for the introduction of the gene of interest into neurons (Mochizuki et al.2001). With regard to safety issues, the genetically modified primate model is simple and safe since the AAV is a non-pathogenic virus. Furthermore, we have already established the procedure for preparing parkinsonian rat and mice models that overexpress mutated α-synuclein using the AAV vector system. Thus, by stereotactically injecting AAV-mutated α-synuclein in the substantia nigra of monkeys; we established a genetically modified primate model with overt hemiparkinsonism in Tukuba primate center. Further analysis will be performed. (240)

  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Furuya T, Hayakawa H, Yamada Y, Yoshimi K, Hisahara S, Miura M, Mizuno Y, Mochizuki H: "Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease."J Neurosci. 25;24(8). 1865-1872 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamada M, Onodera M, Mizuno Y, Mochizuki H: "Neurogenesis revealed by retroviral labeling in normal and MPTP intoxicated olfactory bulb of adult mice."Neuroscience. 173-181 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimo-Nakanishi Y, Hasebe T, Suzuki A, Mochizuki H, Nomiyama T, Tanaka Y, Nagaoka I, Mizuno Y, Urabe T: "Functional Effects of NAD(P)H Oxidase p22phox C242T Mutation in Human Leukocytes and Association with Thrombotic Cerebral Infarction."Atherosclerosis. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Komine-Kobayashi, M, Chou N, Mochizuki H, Nakao A, Mizuno Y, Urabe T: "Dual role of FCR gamma in transient focal cerebral ischemia in mice."Stroke. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamashiro T, Tanaka R, Mochizuki, H, Mizuno Y, Urabe T: "Neurogenesis is after transient global ischemia in the adult hippocampus visualized by improved retroviral vector."Stroke. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Furuya T, Tanaka, R, Urabe T, Hayakawa J, Yamada, M., Migita, M, Shimada T, Mizuno Y, Mochizuki, H: "Establishment of modified chimeric mice using GFP bone marrow as a model for neurological disorders"NeuroReport. 14. 629-632 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mochizuki H, Miura M, Shimada M, Mizuno Y: "AAV-mediated anti-apoptotic gene delivery: In vivo gene therapy for neurological disorders"Methods. 28(2). 248-252 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Suzuki A, Obi K, Urabe T, Hayakawa H, Yamada M, Kaneko S, Onodera M, Mizuno Y, Mochizuki H: "Feasibility of ex vivo gene therapy for neurological disorders using the new retroviral vector GCDNsap packaged in the vesicular stomatitis virus G protein."J Neurochem. 82. 953-960 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka R, Mochizuki H, Suzuki A, Ishitani R, Katsube N, Mizuno Y, Urabe T: "Induction of Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Expression in Rat Brain After Focal lschemia/Reperfusion."J Cereb Blood Flow Metab.. 22. 280-288 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka R, Komine-Kobayashi, M, Mochizuki, H, Yamada, M. Furuya T, Migita, M, Shimada T. Mizuno Y, Urabe T: "Migration of EGFP expressing bone marrow-deribed microglia/macrophage into the mice brain following permanent focal ischemia."Neurosience. 117. 531-539 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Furuya T, Tanaka R, Urabe T, Hayakawa J, Yamada, M., Migita, M, Shimada T, Mizuno Y, Mochizuki, H: "Establishment of modified chimeric mice using GFP bone marrow as a model for neurological disorders"NeuroReort. 14. 629-632 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Choi JB, Uchino H, Azuma K, Iwashita N, Tanaka Y, Mochizuki H, Migita M, Shimada T, Kawamori R, Watada H.: "Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta cells."Diabetologia oct. 46(10). 1366-1374 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochizuki H, Mizuno Y: "Gene therapy for Parkinson's disease"J Neural Transm Suppl. 65. 205-213 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamada M, Onodera M, Mizuno Y, Mochizuki H.: "Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated adult mice."Neuroscience. 124(1). 173-181 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Furuya T, Hayakawa H, Yamada M, Yoshimi K, Hisahara S, Miura M, Mizuno Y, Mochizuki H.: "Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease."J Neurosci. Feb 25. 24(8). 1865-1872 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Komine-Kobayashi M, Chou N, Mochizuki H, Nakao A, Mizuno Y, Urabe T.: "Dual role of Fcgamma receptor in transient focal cerebral ischemia in mice."Stroke. Apr. 35(4). 958-963 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka R, Yamashiro K, Mochizuki H, Cho N, Onodera M, Mizuno Y, Urabe T.: "Neurogenesis After Transient Global Ischemia in the Adult Hippocampus Visualized by Improved Retroviral Vector."Stroke. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimo-Nakanishi Y, Hasebe T, Suzuki A, Mochizuki H, Nomiyama T, Tanaka Y, Nagaoka I, Mizuno Y, Urabe T.: "Functional Effects of NAD(P)H Oxidase p22phox C242T Mutation in Human Leukocytes and Association with Thrombotic Cerebral Infarction."Atherosclerosis. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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