Intravenous non-viral gene therapy for amyotrophic lateral sclerosis

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is the most prevalent lethal motor neuron disease in adults and there is no effective therapy available. The primary defect in ALS is the degeneration of upper and lower motor neurons causing subsequent muscle weakness and atrophy. Neurotrophic factors have potential in therapy for ALS because they show a protective effect on motor neurons in vitro and in vivo. Systemic administration of neurotrophic factors in ALS patients, however, has not shown a therapeutic benefit. This has likely been due to the short half-life of these factors, their poor penetration into the central nervous system and prominent side effects (e.g., flu-like symptoms). Our experimental strategy is focused on a gene therapy approach to deliver therapeutic factors to skeletal muscle and utilize their target derived mechanisms of actions on lower motor neurons. This therapy aims at preserving skeletal muscle functions of limbs and improving the quality of life of the patients with ALS and possibly other motor neuron disorders. Recent improvements in naked plasmid DNA (pDNA) mediated gene transfer into muscle have made this approach clinically viable. Simple intravenous pDNA injection can achieve highly efficient gene expression throughout the limb muscles in a variety of animals, including monkeys, predicting that this procedure will be useful in humans as well. We propose to use intravenous delivery of neurotrophic factor expression vectors to skeletal muscle to improve motor neuron function and survival in the SOD-1 transgenic mouse model for ALS. Our preliminary data suggest that efficient and stable gene transfer can be achieved by this technique. Furthermore, intravenous delivery of pDNA vectors expressing neurotrophic factors (glial-cell derived neurotrophic factor, GDNF; insulin-like growth factor 1, IGF-1) had a therapeutic effect in SOD-1 mice. Since recent data showed that IGF-1 and vascular endothelial growth factor (VEGF) have the best therapeutic effects in SOD-1 mice, we will focus our efforts on IGF-1 and VEGF165 gene transfer. In this STTR phase I proposal we will investigate the distribution of IGF-1 and VEGF165 following intravenous gene transfer, the therapeutic effects (time of onset of disease, motor function, survival) of intravenous neurotrophic factor gene transfer, and the effect on motor neurons (electrophysiology, morphology). Amyotrophic lateral sclerosis (ALS) is the most devastating disease of motor neurons in adults causing progressive weakness and premature death. There is no effective therapy available. We propose a gene therapy approach to deliver therapeutic factors to skeletal muscle and the diseased neurons. This therapy aims at preserving skeletal muscle functions of limbs and improving the quality of life of the patients with ALS and possibly other motor neuron disorders.