1999 Fiscal Year Final Research Report Summary
Adenoviral GDNF gene therapy against motoneuron death
| Project/Area Number |
10670616
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | TOKYO METROPOLITAN ORGANIZATION FOR MEDICAL RESEARCH (1999)
Tokyo Metropolitan Institute for Neuroscience (1998) |
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Principal Investigator |
WATABE Kazuhiko TMIN, Neuropathology, Senior Scientist, 東京都神経科学総合研究所, 副参事研究員 (30240477)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAZOW Yoko TMIN, Neuropathology, Research Associate, 東京都神経科学総合研究所, 主事研究員 (60281705)
OYANAGI Kiyomitsu TMIN, Neuropathology, Senior Scientist, 東京都神経科学総合研究所, 副参事研究員 (00134958)
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| Project Period (FY) |
1998 – 1999
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| Keywords | Adenovirus / Avulsion / Facial nerve / GDNF / Gene therapy / Motoneuron / Motor neuron disease / Spinal cord |
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| Research Abstract |
Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect cranial and spinal motoneurons, that suggests potential uses of GDNF in the treatment of spinal cord injury and motor neuron diseases. We examined neuroprotective effect of human GDNF encoded by an adenovirus vector (AxCAhGDNF) on the death of lesioned adult rat facial and spinal motoneurons. The facial nerve or the seventh cervical segment (C7) ventral and dorsal roots and dorsal root ganglia of adult Fisher 344 rats were avulsed and removed from the stylomastoid or vertebral foramen, respectively, and AxCAhGDNF, AxCALacZ (adenovirus encoding b-galactosidase gene) or PBS was inoculated in the lesioned foramen. One week after the avulsion and treatment with AxCALacZ, the animals showed expression of beta-galactosidase activity in lesioned facial and spinal motoneurons. Animals avulsed and treated with AxCAhGDNF showed intense immunolabeling for GDNF in lesioned facial and spinal motoneurons and expression of virus-induced human GDNF mRNA transcripts in the lesioned brain stem and spinal cord tissues. Nissl-stained cell counts revealed that the treatment with AxCAhGDNF significantly prevented the loss of lesioned motoneurons 2 to 8 weeks after avulsion, as compared to AxCALacZ or PBS treatment. Furthermore, the AxCAhGDNF treatment ameliorated choline acetyltransferase immunoreactivity and suppressed the induction of nitric oxide synthase activity in the lesioned motoneurons after avulsion. These results indicate that the adenovirus-mediated gene transfer of GDNF may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.
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