Delivery of therapeutic genes in motor neuron disease

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DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are fatal motor neuron disorders for which no significant treatments currently exist. Delivery of a therapeutic agent across the blood brain barrier (BBB) to the central nervous system is a significant problem that prevents the effective development of therapies to treat neurodegenerative diseases such as SMA and ALS. Here we propose to develop a simple vascular delivery to transduce genes across the BBB and have an impact on treatment of neurological disorders. We have discovered the unique capacity for the adeno-associated virus (serotype 9) to traverse the BBB and to efficiently target motor neurons and astrocytes within the brain and spinal cord. Here we wish to expand on these studies in mice and to translate them into the non-human primate in order to develop promising therapies for motor neuron disease. Here we propose (1) to optimize the correction of SMA and treatment of ALS in mouse models, (2) to develop a vascular delivery route for motor neuron and astrocytes targeting in the non-human primate and (3) to determine if ALS targets identified in mutant SOD1 mouse models function in human sporadic and familial SOD1 ALS models. We have assembled a team of investigators with all the critical expertise for the study of both SMA and ALS. This proposal includes studies that will not only further the understanding of the biological mechanism of motor neuron disease, but will also lead to the development of a technique for vascular delivery of therapeutics that will have widespread impact for many neurological disorders. PUBLIC HEALTH RELEVANCE: This delivery system will revolutionize therapies for all neurological disorders. We will specifically focus on the two major motor neuron disorders, Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS). The delivery of SMN in SMA will have a major benefit.