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

作者：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

来源：Molecular Therapy, 2008, 16(6): 1056-1064.

DOI：10.1038/mt.2008.60

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.

• 出版日期2008-6