Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease.

Abstract

Neuromuscular/neurodegenerative disorders, such as the death of spinal cord motor neurons in amyotrophic lateral sclerosis (ALS) or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. We have found that in mixed rat embryonic spinal cord cultures or in purified motor neuron preparations, recombinant human insulin-like growth factor 1 (rhIGF-1) enhances the survival of motor neurons at EC50 concentrations of 2 nM, consistent with an interaction at the tyrosine kinase-coupled rhIGF-1 receptor. In a model of programmed cell death in ovo, administration of rhIGF-1 produces a marked survival of motor neurons. In a variety of models of predominantly motor neuron or nerve injury in rodents, administration of rhIGF-1 prevents the death of motor neurons in neonatal facial nerve lesions, attenuates the loss of cholinergic phenotype in adult hypoglossal nerve axotomy and hastens recovery from sciatic nerve crush in mice. In a genetic model of motor neuron compromise, the wobbler mouse, rhIGF-1 (1 mg/kg s.c. daily) delayed the deterioration of grip strength and provided for a more normal distribution of fibre types. In addition, rhIGF-1 (0.3-1.0 mg/kg s.c. daily) prevents the motor and/or sensory neuropathy in rodents caused by vincristine, cisplatinum or Taxol. These combined data indicate that rhIGF-1 has marked effects on the survival of compromised motor neurons and the maintenance of their axons and functional connections. They also suggest the potential utility of rhIGF-1 for the treatment of diseases such as ALS and certain neuropathies.