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The Journal of Neuroscience, August 15, 2002, 22(16):6920-6928

Neuroprotective Effects of Glial Cell Line-Derived Neurotrophic Factor Mediated by an Adeno-Associated Virus Vector in a Transgenic Animal Model of Amyotrophic Lateral Sclerosis

Li-Jun Wang^{1, 2}, Yan-Yan Lu^{1, 2}, Shin-ichi Muramatsu¹, Kunihiko Ikeguchi¹, Ken-ichi Fujimoto¹, Takashi Okada², Hiroaki Mizukami², Takashi Matsushita², Yutaka Hanazono², Akihiro Kume², Toshiharu Nagatsu³, Keiya Ozawa², and Imaharu Nakano¹

¹ Division of Neurology, Department of Medicine and ² Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan, and ³ Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive lethal disease that involves selective annihilation of motoneurons. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for ALS and other motor neuron diseases. Because adeno-associated virus (AAV) has been developed as an attractive gene delivery system with proven safety, we explored the therapeutic efficacy of intramuscular delivery of the GDNF gene mediated by an AAV vector (AAV-GDNF) in the G93A mouse model of ALS. We show here that AAV-GDNF leads to substantial and long-lasting expression of transgenic GDNF in a large number of myofibers with its accumulation at the sites of neuromuscular junctions. Detection of GDNF labeled with FLAG in the anterior horn neurons, but not -galactosidase expressed as a control, indicates that most of the transgenic GDNF observed there is retrogradely transported GDNF protein from the transduced muscles. This transgenic GDNF prevents motoneurons from their degeneration, preserves their axons innervating the muscle, and inhibits the treated-muscle atrophy. Furthermore, four-limb injection of AAV-GDNF postpones the disease onset, delays the progression of the motor dysfunction, and prolongs the life span in the treated ALS mice. Our finding thus indicates that AAV-mediated GDNF delivery to the muscle is a promising means of gene therapy for ALS.

Key words: amyotrophic lateral sclerosis; motoneuron; adeno-associated virus vector; glial cell line-derived neurotrophic factor; gene therapy; retrograde transport

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166920-09$05.00/0

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