G.P.11.07 AAV mediated gene transfer of IGF-1 and VEGF to the ventricular system provides significant therapeutic benefit in a mouse model of amyotrophic lateral sclerosis

Abstract

Amytrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by a selective loss of motor neurons in the motor cortex, brain stem and spinal cord. Currently there is no effective therapy for the treatment of ALS. Although a number of studies have demonstrated that neurotrophic factors have potent effects on motor neuron survival their delivery to the CNS remains to be a challenge. Recently it has been reported that AAV serotype 4 has an enhanced affinity for different cell types of the ventricular system including the ependymal cell layer and choroid plexus. In this study, we wished to determine if neurotrophic factor gene delivery to the ventricular system would be an effective strategy for delivering neurotrophic factors to the CNS of ALS mice in order to modify disease progression. Specifically, we evaluated the efficacy of intraventricular delivery of AAV4–IGF-1 and AAV4–VEGF in 90-day-old SOD1G93A mice. Starting at 80 days of age (and every 10 days thereafter), SOD1G93A mice underwent behavioral testing (rotarod, hindlimb and forelimb grip strength) to assess motor function. At 90 days of age (i.e., time point at which SOD1 mice exhibit overt disease symptoms of ALS) mice received intraventricular injection of AAV4–IGF-I, AAV4–VEGF, or AAV4–GFP. We found that delivery of neurotrophic expressing AAV4 vectors (regardless of transgene) significantly improved motor performance in both rotarod and grip strength behavioral tests and significantly extended lifespan (i.e., 20 days). Treatment with AAV4–GFP had no effect on any of the parameters mentioned above. Our results indicate that intraventricular injection of neurotrophic expressing AAV4 vectors is an effective approach for modifying disease progression in a mouse model of ALS.