This project aims to help patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), which involves the progressive and relatively rapid death of specific cells (called motor neurons) in the brain and spinal cord and the loss of connections made by the spinal cord motor neurons to the muscle. Previous reports have shown that a powerful growth factor called glial cell-line derived neurotrophic factor (GDNF) can slow disease progression in several mouse models of ALS, and we have very recently shown that GDNF delivered to the muscle can also slow disease progression in a larger rat model of the disease. In this current study, we hope to delay disease progression in rats with an inherited form of ALS by delivering GDNF directly to the muscle using a gene therapy approach. A rigorous and extensive set of experiments will be performed to allow us to apply to the Food and Drug Administration for approval to move this approach into humans. An inactivated, benign virus will be engineered to produce GDNF in collaboration with UniQure. The virus will then be injected into the muscle of diseased animals to deliver GDNF at different concentrations to establish the maximum effective dose. Finally, we will move to non-human primate to perform studies in larger animals that have a limb size closer to humans to optimize the best way to deliver GDNF and to determine how many injection sites are needed.

The potential clinical applications are clearly to treat ALS patients with this novel therapy. The benefits are a reduction in spinal cord motor neuron death leading to sustained muscle strength over time. The risks are a reaction to the virus, even though it has been inactivated, or to the GDNF it is producing, even though the optimal dose will have been evaluated. Furthermore, the principal investigator of this proposal has been involved with previous clinical trials using GDNF in patients with Parkinson's disease where there were no serious side effects following 3 years of delivering the GDNF protein. We predict that following Investigational New Drug approval there will be a 1-year open Phase I clinical trial where GDNF will be virally delivered to the leg muscles of ALS patients. Therefore, from the time of funding it should take 4 years to see if this is safe in man and perhaps has some efficacy in the targeted leg muscles. This would then be followed by a larger blinded Phase II study aimed at establishing efficacy. There is a very strong rationale for why this growth factor may work and a good possibility it will have positive effects based on all of the animal studies performed to date. As such, we feel that this study will contribute greatly to advancing the development of a much needed new therapeutic approach for ALS.

We should point out that the current proposal is part of a wider set of experimental approaches aimed at using GDNF to protect all parts of the degenerating nervous system in ALS. We are working in parallel towards a clinical trial to inject human neural stem cells secreting GDNF into the spinal cord of ALS patients. This may protect the spinal cord motor neurons (as in the currently proposed study), as well as their projections to the muscle, which represents a very powerful approach to this devastating disease. Finally, we are also conducting animal studies aimed at delivering stem cells secreting GDNF to protect the motor neurons in the brain also affected in ALS. The currently proposed study does not directly protect these brain motor neurons as this circuit may not be as crucial for paralysis if the spinal cord motor neurons and spinal/muscular connections are protected.