Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy.
Amyotrophic lateral sclerosis (ALS) is caused by a progressive degeneration of motor neurons. The cause of sporadic ALS is not known, but 1-2% of all cases are familial and caused by mutations in the copper-zinc superoxide dismutase (SOD1) gene. Transgenic SOD1 mice serve as a transgenic mouse model for these cases. Glial cell-derived neurotrophic factor (GDNF) has a potent trophic effect on motor neurons. Clinical trials in which growth factors have been systemically administered to ALS patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. Gene transfer of therapeutic factors to motor neurons and/or their target cells, such as muscle, may overcome these problems. Previously, we and others have shown that intramuscularly administered adenovirus vector (AVR) results in foreign gene expression not only in muscle cells, but also in relevant motor neurons in the spinal cord, because of retrograde axonal transport. In this study we utilized an AVR to introduce GDNF into muscles of neonatal SOD1 mice. We showed that AVR-mediated GDNF expression delayed the onset of disease by 7 +/- 8 days (mean +/- SD), prolonged survival by 17 +/- 10 days, and delayed the decline in motor functions (as determined on a rotating rod) by 7-14 days. These results demonstrate that gene delivery to muscle and motor neurons has the potential to treat devastating neurodegenerative diseases such as ALS.
Acsadi
Gyula
G
Department of Pediatrics, Center for Molecular Medicine and Genetics, Wayne State University, School of Medicine, 3901 Beaubien Road, Detroit, MI 48201, USA. gacsadi@med.wayne.edu
Anguelov
Roumen A
RA
Yang
Huibin
H
Toth
Gabor
G
Thomas
Ronald
R
Jani
Agnes
A
Wang
Yuying
Y
Ianakova
Emilia
E
Mohammad
Sulaiman
S
Lewis
Richard A
RA
Shy
Michael E
ME
D000256:Adenoviridae / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000628:therapy*; D000818:Animals; D004594:Electrophysiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1