Drug Development

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.