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.

Key words::

• PEGylated IGF-1
• SOD mice
• insulin-like growth factor I
• ALS mouse models

Acknowledgements

We are very grateful to the Roche technical team for providing PEG-IGF-I. We further thank Eginhard Schick for analytical support, the behavioural group at PsychoGenics for their assistance in dosing and tissue collections, and Gerhard Binder for providing radiolabelled rhIGF-II.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.