Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity.

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-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.

• Authors: James C Dodge, Amanda M Haidet, Wendy Yang, Marco A Passini, Mark Hester, Jennifer Clarke, Eric M Roskelley, Christopher M Treleaven, Liza Rizo, Heather Martin, Soo H Kim, Rita Kaspar, Tatyana V Taksir, Denise A Griffiths, Seng H Cheng, Lamya S Shihabuddin, Brian K Kaspar
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 16 Issue 6 Pg. 1056-64 (Jun 2008) ISSN: 1525-0024 [Electronic] United States
• PMID: 18388910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha
• Insulin-Like Growth Factor I

Topics

• Amyotrophic Lateral Sclerosis (genetics, therapy)
• Animals
• Cell Survival
• Central Nervous System (cytology, metabolism)
• Cerebellum (metabolism)
• Dependovirus (genetics)
• Female
• Genetic Therapy (methods)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Male
• Mice
• Neurodegenerative Diseases (metabolism)
• Neuroglia (cytology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)