? ? Amyotrophic lateral sclerosis (ALS) is a lethal neuromuscular disease that is associated with the degeneration of spinal and brainstem motor neurons (MNs), leading to atrophy of limb, axial and respiratory muscles. The cause of ALS is unknown, and there is no effective therapy. Factors that generally act to protect neurons from cell death, including neurotrophic factors (NTFs), are obvious candidates for therapeutic evaluation in ALS. While the chronic delivery of large molecules directly to the CNS has proven to be a major obstacle for therapy of CNS diseases, we recently discovered that recombinant adeno-associated viral vectors (AAV) expressing therapeutic genes can be retrogradely transported efficiently from muscle to MNs of the spinal cord. We utilized this novel transport system to deliver glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor-1 (IGF-1) to spinal MNs to test their effects in an animal model of ALS. We report that IGF-1 prolongs life and delays disease progression, even when delivered at the time of overt disease symptoms in an ALS animal model. In addition, IGF-1 significantly slows the initiation of the apoptotic process in this disease model. Clinical trials are currently being designed to test this potential therapy in patients with ALS. This proposal seeks to translate the basic science discoveries we have made into a clinical study of AAV-IGF-1 in subjects with ALS.
We aim to complete further efficacy studies as well safety and toxicity studies required for the submission of an Investigational New Drug Application (IND) for a clinical study of AAV-IGF-1 in adults with ALS. ? ?
