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

ABSTRACT: 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, amiR^Tau01, 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 amiR^Tau01-mediated MAPT knockdown in individual neurons; however, vector biodistribution in the NHP brain

SUBMITTER: Hogestyn JM 

PROVIDER: S-EPMC12703150 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature