title: Functional improvement in mouse models of familial amyotrophic lateral sclerosis by PEGylated insulin-like growth factor I treatment depends on disease severity.
abstract: Insulin-like growth factor I (IGF-I) has been successfully tested in the SOD1-G93A mouse model of familial amyotrophic lateral sclerosis (ALS) and proposed for clinical treatment. However, beneficial effects required gene therapy or intrathecal application. Circumventing the dosing issues we recently found that polyethylene glycol (PEG) modified IGF-I (PEG-IGF-I) modulated neuromuscular function after systemic application, and protected against disease progression in a motor neuron disease model. Here we investigated its effects in two SOD1-G93A mouse lines, the G1L with a milder and the G1H with a more severe phenotype. Results showed that in G1L mice, PEG-IGF-I treatment significantly improved muscle force, motor coordination and animal survival. In contrast, treatment of G1H mice with PEG-IGF-I or IGF-I even at high doses did not beneficially affect survival or functional outcomes despite increased signalling in brain and spinal cord by both agents. In conclusion, the data point towards further investigation of the therapeutic potential of PEG-IGF-I in ALS patients with less severe clinical phenotypes.
authors.affiliation: F. Hoffmann-La Roche Ltd., CNS Pharma Research & Early Development, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Saenger
authors.forename: Bettina
authors.initials: B
authors.lastname: Holtmann
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nilges
authors.forename: Susanne
authors.initials: S
authors.lastname: Schroeder
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeflich
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Kletzl
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Susanne
authors.initials: S
authors.lastname: Ostrowitzki
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D007334:Insulin-Like Growth Factor I