TITLE

Delivery of AAV-IGF-1 to the CNS Extends Survival in ALS Mice Through Modification of Aberrant Glial Cell Activity

AUTHOR(S)
Dodge, James C.; Haidet, Amanda M.; Yang, Wendy; Passini, Marco A.; Hester, Mark; Clarke, Jennifer; Roskelley, Eric M.; Treleaven, Christopher M.; Rizo, Liza; Martin, Heather; Kim, Soo H.; Kaspar, Rita; Taksir, Tatyana V.; Griffiths, Denise A.; Cheng, Seng H.; Shihabuddin, Lamya S.; Kaspar, Brian K.
PUB. DATE
June 2008
SOURCE
Molecular Therapy;Jun2008, Vol. 16 Issue 6, p1056
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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-α (TNF-α) 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.Molecular Therapy (2008) 16 6, 1056–1064 doi:10.1038/mt.2008.60
ACCESSION #
35349600

 

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