Global spinal cord trophic factor delivery using intracerebral rAAV in ALS rats

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DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a progressive and lethal neurological disorder characterized by death of upper and lower motoneurons. There is no known cure. Our group has experience using viral vectors to deliver proteins in animal models of neurological disorders and have proceeded to clinical trials in other medical indications. Recent reports indicate that glial cell line- derived neurotrophic factor (GDNF) and insulin-like growth factor 1 (IGF1) are trophic factors that may be efficacious in treating ALS. However, since ALS is progressive, chronic protein delivery will be needed. Moreover, the affected motoneurons are distributed in the ventral horn of the entire spinal cord. Chronic delivery and global spinal cord delivery are major challenges for protein delivery. The goal of this project is to use recombinant adeno-associated viral vectors, injected in single brain regions, to deliver the secreted trophic factors GDNF and IGF1 to the entire spinal cord, by using anterograde transport via known anatomical spinal projecting tracts. The overall hypothesis of the present proposal is that either the pyramidal cells of the motor cortex or the neurons in the red nucleus can be permanently transduced by recombinant adeno-associated viral vectors (rAAV) to produce GDNF and IGF1 and these proteins can be delivered to the entire spinal cord in a therapeutic manner. Therefore, two aims are proposed: 1) To determine the efficiency, duration and safety of anterograde transport of the reporter gene, green fluorescent protein (GFP), IGF1, and GDNF after injection of rAAV1, rAAV5 and rAAV8 into the red nucleus in normal rats. In order to optimize spinal cord delivery of gene products. 2) To examine the potential for rescue of lower motor neuron disease in an amyotrophic lateral sclerosis rat model using rAAV-delivered GDNF and IGF1. Rescue will be determined both by evaluating the progression of the motor symptoms in control and ALS rats and by detailed histopathology of the spinal cord. The present proposal is likely to produce a significant amount of general information about vector-mediated protein delivery to the entire spinal cord. These data may have general implications for spinal cord injuries and ALS in particular.