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An Investigational RNAi Therapeutic for Tau Lowering.

Authors :
Farley, Jonathan
Haines, Jeffery D
Gannon, Sean
Nguyen, Tuyen
Abbott, Stephen
Darcy, Justin
Tymon, Roxanne
Cha, Diana
Schlegel, Mark
Castoreno, Adam
Bisbe, Anna
Zlatev, Ivan
Rollins, Jeff
Bostwick, Bret
Avbersek, Andreja
Macdonald, Lynn
Gao, Min
Anderson, Matthew
Brown, Kirk
Source :
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 21, Vol. 19 Issue 21, p1-1, 1p
Publication Year :
2023

Abstract

Background: The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a class of progressive neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's Disease (AD). There is a high unmet medical need for new approaches to target Tau in these numerous tauopathies. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs. Method: Here, using our lipophilic C16‐conjugated siRNA for CNS delivery, we identified potent molecules targeting the MAPT gene in both in vitro and in vivo models. Results: Our RNAi molecules targeting the MAPT gene durably reduce MAPT mRNA and Tau protein levels in both in vitro and in vivo model systems. Furthermore, in a 16‐week non‐human primate study, we observed robust target engagement resulting in sustained reduction of MAPT transcript and Tau protein in brain tissue and cerebrospinal fluid. Conclusion: Together, these results suggest that RNAi lowering of Tau could be a novel strategy to address both intra‐ and extra‐cellular accumulation of Tau aggregates, which could have therapeutic advantages for treating tauopathies. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15525260
Volume :
19
Issue :
21
Database :
Supplemental Index
Journal :
Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Publication Type :
Academic Journal
Accession number :
174415513
Full Text :
https://doi.org/10.1002/alz.074204