Insulin-like growth factor system in amyotrophic lateral sclerosis

Insulin-like growth factor-I (IGF-I) is a neurotrophic factor with insulin-like metabolic activities, and possesses potential clinical applications, particularly in neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a chronic progressive devastating disorder of the central nervous system, characterized by the death of upper and lower motor neurons. Both in vivo and in vitro studies have shown that IGF-I promotes motor neuron survival and strongly enhances motor nerve regeneration. Evidence that IGF-I rescues motor neurons has led to clinical trials of human recombinant IGF-I in ALS patients. However, systemic delivery of human recombinant IGF-I in these trials did not lead to beneficial clinical effects in ALS patients and may be due through inactivation of IGF-I by binding to IGF binding proteins (IGFBPs), and or limited delivery of IGF-I to motor neurons. Recently it was shown that both IGF-I receptors and IGFBPs were increased on motor neurons of ALS patients and free levels of IGF-I were decreased by 50%. In this study it was suggested that IGFBPs inactivate IGF-I by forming inactive complexes. The uses of IGF analogues with low affinity for IGFBPs and analogues that are able to displace IGF-I from IGFBPs are better candidates in new clinical trials. Another possibility is to find a way of IGF-I transport without hindrance of circulating and tissue-specific IGFBPs, such as IGF-I delivery based on gene therapy.