UC San Diego

Gene therapy is being explored for its potential to treat neurodegenerative diseases such as Alzheimer’s Disease and Huntington’s Disease through the delivery of therapeutic transgenes with Adeno-Associated Virus (AAV) vectors. The leading candidates for these treatments are AAV9 and AAV-PhP.eB because of their safety, efficacy in rodent and non-human primate studies, and their ability to cross the blood-brain barrier. These vectors have been tested in juvenile mice, but neurodegenerative diseases typically affect older individuals and these vectors have never been tested in aged mice. Therefore, we delivered AAV9-eGFP and AAV-PhP.eB-eGFP intrathecally or intravenously to mice and compared the virus’ transduction patterns in the brain across aging, using groups of aged 20-month-old mice versus juvenile 3-month-old mice. We found a reduction in gene expression with aging in mice treated with intravenous AAV9. However, there was no detectable change in gene expression across aging in mice receiving intravenous AAV-PhP.eB or intrathecal AAV9. There is a significant reduction associated with increased weight when mice are treated with intravenous AAV9 but not with intrathecal AAV9, indicating that the reduced efficacy of intravenous AAV9 in aged mice may be due to the larger size of these animals. These results suggest that the more promising delivery method for AAV9 gene therapy in older individuals is via the intrathecal route.