title: 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.affiliation: Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA. jim.dodge@genzyme.com
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Haidet
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
authors.forename: Mark
authors.initials: M
authors.lastname: Hester
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.forename: Eric M
authors.initials: EM
authors.lastname: Roskelley
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Treleaven
authors.forename: Liza
authors.initials: L
authors.lastname: Rizo
authors.forename: Heather
authors.initials: H
authors.lastname: Martin
authors.forename: Soo H
authors.initials: SH
authors.lastname: Kim
authors.forename: Rita
authors.initials: R
authors.lastname: Kaspar
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Taksir
authors.forename: Denise A
authors.initials: DA
authors.lastname: Griffiths
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: 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
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I