An Investigational RNAi Therapeutic for Tau Lowering

Abstract Background The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a group of progressive, neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia, progressive supranuclear palsy, and Alzheimer’s Disease. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs. Method Here, using our clinically validated C16‐siRNA CNS delivery platform, we have identified potent molecules targeting the MAPT gene. Result We have identified potent molecules that durably reduce MAPT mRNA and Tau protein in both in vitro and in vivo model systems. Furthermore, in a non‐human primate study, we demonstrated robust, sustained reduction of MAPT transcript and tau protein in disease relevant brain tissue that was well‐tolerated through 16‐weeks. Conclusion Together, these results suggest that Tau‐lowering via C16‐siRNAi may provide a novel strategy to reduce, and potentially reverse, accumulation of intracellular and extracelluar Tau aggregates. This approach has advanced into in IND‐enabling development.