AAV delivery of artificial miRNA targeting MAPT for the reduction of tau pathology in Alzheimer's disease.

Tau reduction is a promising therapeutic approach with the potential to slow the progression of Alzheimer's disease. Here, we propose adeno-associated viral (AAV) delivery of an artificial miRNA (amiRNA) targeting the microtubule-associated protein tau (MAPT) mRNA for sustained tau reduction with a single therapeutic injection. Out of 22 initial designs, we identified potent, accurately processed, and highly specific amiRNA candidates. Our lead, amiRTau01, significantly reduced pathological forms of phosphorylated tau in the brain and spinal cord of the Tau22 tauopathy mouse model. In a nonhuman primate study using the novel capsid AAV.GMU01, we demonstrated clear amiRTau01-mediated MAPT knockdown in individual neurons; however, vector biodistribution in the NHP brain was insufficient to drive MAPT reduction in bulk tissue. Our findings support amiRTau01 as a potent therapeutic amiRNA, warranting development of new capsids with improved brain biodistribution to facilitate clinical development for Alzheimer's disease.