596. AAV Gene Delivery of the Anti-Tau Antibody PHF1 Reduces Brain Tau Pathology in P301L Mice

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Anti-tau immunotherapy has been proposed as a promising therapy for various tauopathies including Alzheimer's disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). However, there are limitations to passive immunization including the need for repeated administration and the very low levels of antibody that get into brain from the circulation. To circumvent the disadvantages of passive immunization, we have used serotype rh. 10 adeno-associated virus vectors to deliver an anti-tau monoclonal antibody PHF1, known to reduce tau pathology following passive immunization in several tauopathy mouse models directly to the CNS. To accomplish this, we stereotactically administered 1010 viral genomes (vg) of AAVrh. 10-PHF1 or AAVrh. 10-mCherry as a control, bilaterally into the hippocampus of young (3.5-month old) homozygous P301L mice, a model that develops robust tau pathology in an age- and brain region-dependent manner. Six months after injection, mice were sacrificed to measure the presence of anti-tau antibody as well as the effects of treatment on tau pathology in several brain regions using specific ELISAs and immunohistochemistry (IHC) for quantifying pathological and normal tau. In pilot experiments using wild-type C57BL/6 and P301L mice, we observed much higher levels of PHF1 antibody in the hippocampus when delivered via the AAVrh. 10 vector compared to passive immunization (3100-fold higher). We observed that treatment with AAVrh. 10-PHF1 resulted in a marked antibody-dependent reduction in tau pathology in P301L mice, including a highly significant reduction in tau pathology in the hippocampus (≥80-90% p=0.001) compared to the control vector. There was also no reduction in total tau measured by ELISA in any brain region examined. Based on these observations, AAVrh. 10 gene delivery of anti-tau monoclonal antibodies to the CNS may represent a novel therapeutic strategy for treating various tauopathies including FTD, PSP and AD.