Therapeutic effects of PEGylated insulin-like growth factor I in the pmn mouse model of motoneuron disease

Abstract Based on its potent neurotrophic and myotrophic activities, insulin-like growth factor I (IGF-I) has been proposed for treatment of neuromuscular disorders such as muscular dystrophies and amyotrophic lateral sclerosis (ALS). However, the short half life in the circulation limits its use in vivo . At least in mouse models, beneficial effects are generally only observed by dosing regimens such as minipumps or gene therapy that are difficult to translate to patients. We have developed a polyethylene glycol coupled IGF-I (PEG-IGF-I) that could circumvent these problems by longer half-life, showing all features of a therapeutic agent supporting muscular and neuronal function. Here we investigated its effects in the pmn mutant mouse, a model with typical dying-back motoneuron degeneration. In vitro , PEG-IGF-I and rhIGF-I profoundly promoted survival axonal growth of wild-type as well as pmn mutant embryonic motoneurons, suggesting that PEG-IGF-I had a fully conserved neurotrophic activity via its receptor. In vivo , treatment of pmn mutant mice with PEG-IGF-I prolonged survival, protected against late stage weight loss and significantly maintained muscle force and motor coordination. Consistently, PEG-IGF-I treatment rescued facial and lumbar motoneurons from cell death and partially preserved phrenic nerve myelinated axons. The data support that PEG-IGF-I could be used for treatment of neuromuscular diseases in a clinically feasible manner.