TITLE: Directed Evolution of Novel AAV Capsids for Global CNS Delivery in Rodents and Primates ABSTRACT Many monogenic based neurological disorders present attractive targets for gene therapy, but even with promising proof-of-concept rodent studies, successful clinical translation depends upon efficient transgene delivery and expression across the entire central nervous system (CNS). Directed evolution is a powerful and proven method to develop novel adeno-associated virus (AAV) vector capsids that exhibit properties distinct from naturally occurring serotypes. However, to date, the majority of novel capsids have been derived in rodents or in vitro models whose properties may or may not translate to other species, in particular primates. This proposal will utilize AAV capsid DNA shuffling directed evolution to develop gene delivery vectors for a number of human CNS disease applications. To do this, parallel selections and recovered clone characterization will be carried out in mice and non-human primates (NHPs), combining the expertise of experts on both CNS gene transfer in NHPs and AAV vector design. The experimental plan should independently generate superior AAV capsids capable of global CNS delivery, with cross-compatibility between mice and NHPs. Moreover, we have designed our experimental approach to generate vectors that exhibit selective tropism for neurons, astrocytes, and/or oligodendrocytes, which would be invaluable reagents for research and therapeutic applications. If successful, the AAV capsid reagents generated should create new research tools, broaden the application of gene therapy to more CNS disorders, and facilitate the translation of existing CNS gene therapy approaches to humans.
TITLE: Directed Evolution of Novel AAV Capsids for Global CNS Delivery in Rodents and Primates PROJECT NARRATIVE This project aims to make novel virus-based gene delivery vehicles (AAVs) that are specifically engineered to treat brain and spinal cord diseases. If successful, these new basic research and clinical tools will greatly facilitate the testing and application of gene therapy approaches in animal models and humans, with broad application towards numerous diseases such as inborn metabolic disorders, spinal muscular atrophy, and Alzheimer's. We will utilize a virus-based gene delivery platform that has been used in over 70 human clinical trials, and tailor these gene delivery vehicles to be administered by a single intrathecal injection, a routine outpatient procedure.