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Intramuscular injection of AAV-GDNF results in sustained expression of transgenic GDNF, and its delivery to spinal motoneurons by retrograde transport

Posted by on in 2003
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 Neuroscience Research Volume 45, Issue 1 , January 2003, Pages 33-40
Yan-Yan Lu (a)(b)(1), Li-Jun Wang (a)(b), Shin-ichi Muramatsu (a), Kunihiko Ikeguchi (a), Ken-ichi Fujimoto (a), Takashi Okada (b), Hiroaki Mizukami (b), Takashi Matsushita (b), Yutaka Hanazono (b), Akihiro Kume (b), Toshiharu Nagatsu (c), Keiya Ozawa (b) and Imaharu Nakano (a)
(a) Division of Neurology, Department of Medicine, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Tochigi 329-0498, Japan
(b) Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Tochigi 329-0498, Japan
(c) Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
Received 11 July 2002; accepted 13 September 2002; Available online 19 December 2002.
(1) Stem Cell Research Center, Health Science Center, Peking University, Beijing 100083, People's Republic of China .


Adeno-associated virus (AAV) vector has been developed as an attractive gene delivery system with proven safety. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The purpose of this report was to investigate transgenic GDNF expression at different time points post AAV mediated GDNF intramuscular delivery. An AAV vector was constructed to encode a recombinant fusion of GDNF tagged with a FLAG sequence at the C-terminal (AAV-GDNF) to distinguish it from its endogenous counterpart. A single intramuscular injection of AAV-GDNF led to substantial expression of transgenic GDNF which remained for at least 10 months in transduced gastrocnemius muscle. This transgenic GDNF was distributed in a large number of myofibers, mainly in the vicinity of the sarcolemma and predominantly concentrated at the sites of neuromuscular junctions (NMJs). Furthermore, transgenic GDNF, but not -galactosidase expressed as a control, was detected in the motoneurons that projected axons to the injected muscles, thus, indicating retrograde axonal transportation of the transgenic GDNF. This study provides a basis for a strategy of intramuscular AAV-GDNF delivery to protect motoneurons as a possible means of ALS treatment.

Author Keywords: Adeno-associated virus (AAV); Glial cell line-derived neurotrophic factor (GDNF); Gene therapy; Motoneurons; Intramuscular injection; Retrograde transport

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