Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models of ALS has shown that insulin-like growth factor-1 (IGF-1) slows disease progression when delivered at disease onset. However, IGF-1's mechanism of action along the neuromuscular axis remains unclear. In this study, symptomatic ALS mice received IGF-1 through stereotaxic injection of an IGF-1-expressing viral vector to the deep cerebellar nuclei (DCN), a region of the cerebellum with extensive brain stem and spinal cord connections. We found that delivery of IGF-1 to the central nervous system (CNS) reduced ALS neuropathology, improved muscle strength, and significantly extended life span in ALS mice. To explore the mechanism of action of IGF-1, we used a newly developed in vitro model of ALS. We demonstrate that IGF-1 is potently neuroprotective and attenuates glial cell-mediated release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO). Our results show that delivering IGF-1 to the CNS is sufficient to delay disease progression in a mouse model of familial ALS and demonstrate for the first time that IGF-1 attenuates the pathological activity of non-neuronal cells that contribute to disease progression. Our findings highlight an innovative approach for delivering IGF-1 to the CNS.
Dodge
James C
JC
Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA. jim.dodge@genzyme.com
Haidet
Amanda M
AM
Yang
Wendy
W
Passini
Marco A
MA
Hester
Mark
M
Clarke
Jennifer
J
Roskelley
Eric M
EM
Treleaven
Christopher M
CM
Rizo
Liza
L
Martin
Heather
H
Kim
Soo H
SH
Kaspar
Rita
R
Taksir
Tatyana V
TV
Griffiths
Denise A
DA
Cheng
Seng H
SH
Shihabuddin
Lamya S
LS
Kaspar
Brian K
BK
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D002470:Cell Survival; D002490:Central Nervous System / Q000166:cytology* / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I