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

• Published in: Molecular therapy Vol. 16; no. 6; pp. 1056 - 1064
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2008; Elsevier Limited
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - therapy; Animals; Cell Survival; Central Nervous System - cytology; Central Nervous System - metabolism; Cerebellum - metabolism; Dependovirus - genetics; Female; Genetic Therapy - methods; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Male; Mice; Neurodegenerative Diseases - metabolism; Neuroglia - cytology; Neuroglia - metabolism; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Vectors (Biology); United States > US; Massachusetts; Ohio
• DOI: 10.1038/mt.2008.60
• ISSN: 1525-0016

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.