Gene Therapy Delivery for Age-related Neurodegenerative Diseases

Project Summary/Abstract Age-related neurodegenerative disorders, such as Alzheimer’s disease and related tauopathies, are a major therapeutic challenge. There are critical brain regions implicated in disease pathogenesis and overtime the whole or a large portion of the brain is affected. Therefore, both a focal and broad brain treatment approach is needed to achieve long-term therapeutic benefit. Gene therapy is the use of genetic material to target disease etiology. Viral vectors are used to deliver therapeutic genes to cells to provide long-lasting intervention from a single treatment. Recombinant adeno-associated virus (rAAV) vectors are highly used due to their efficient gene transfer, broad serotype-dependent tropism, low risk of insertional mutagenesis, and long-term transgene expression in non-dividing cells, such as neurons. AAV9 is currently the most frequently used serotype for treating neurological disorders as it can be delivered in blood or cerebral spinal fluid to broadly transduce the brain in a dose-dependent manner. Direct brain injections are effective for focal brain treatments, but are an invasive procedure. With non-invasive systemic delivery, high vector doses are needed to achieve sufficient brain transduction in adults. The greater the number of viral particles received increases the risk of severe immune responses and inhibits use in adults due to manufacturing considerations. We and others have demonstrated that use of FUS to open the BBB can significantly reduce systemic vector doses and target rAAV vectors to select brain regions. While promising for focal treatments, this then limits the ability of AAV9 to efficiently transduce non-targeted brain regions. CSF delivery of AAV9 significantly reduces the amount of vector needed to achieve equivalent or greater brain transduction compared to systemic delivery and achieves high CNS transduction relative to the site of injection. Therefore, we predict that IT delivery of AAV9 combined with transcranial FUS will allow for both focal and broad targeting of gene therapies to the brain and be an effective delivery approach for age-related neurodegenerative diseases. This grant will develop the use of combined FUS and IT injection as an efficient delivery method of AAV vectors to the brain, define mechanisms for this enhancement, determine vector capsid and promoter usage, and test this application in a mouse model of tauopathy. If we are successful, this approach can be readily translated for treating neurodegenerative diseases.