Gene Targeting and Regulation for Neurological Disease

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DESCRIPTION (provided by applicant): Therapeutic advances utilizing gene therapy vectors have recently shown great promise in a number of pre-clinical studies of neurological disorders. The central nervous system, however, presents unique challenges for the development of successful gene therapy approaches and advancement of this therapeutic modality to the clinic. To accelerate gene therapy applications into the clinic, several issues remain to be further examined and resolved. One major issue that has raised significant concern in gene therapy is long-term safety. A second issue that requires further research is the development of efficient delivery strategies to target diseased regions of the brain. Thirdly, effective methods for both long-term and controlled expression of therapeutic transgenes need to be developed. Assessment of the efficacy and safety of proposed methodological advances would require pre-clinical testing in animal models of neurodegenerative disorders. We have recently discovered that adeno-associated vectors (AAV) have the unique property of retrograde transport within the nervous system and we have utilized this finding to efficiently deliver therapeutic transgenes to distinct regions of the brain. Furthermore, we have recently engineered a novel regulatable AAV vector system that allows control of transgene expression. The novelty of the system allows genes to be rapidly turned on with one ligand and rapidly turned off by a second, different ligand. In this project, we propose to develop efficient, targeted gene delivery to the nervous system and test the recrulatable AAV vector system for in vitro and in vivo applications. We will assess the ability of this system to efficiently deliver therapeutic transgenes that will prevent or slow cell death occurring in neurodegenerative diseases, and utilize this new methodology to determine therapeutic windows for intervening in disease progression.