MAPT splicing modulators reduce 4R tau and rescue tauopathy phenotypes in human neurons and in a mouse model.

Authors

M Catarina Silva, Hannah Lindmeier, Paolo Pigini, Jennifer Laughlin, Yong Yu, Christie Morrill, Michael A Arnold, Scott J Barraza, Khalil Saadipour, Monal Dieterich, Angela Minnella, Lin-Ing Wang, Wencheng Li, Kausiki Datta, Nanjing Zhang, Jana Narasimhan, Christopher R Trotta, Matthew G Woll, Ellen M Welch, Kellie Benzow, Kul Karanjeet, Steven Lotz, Taylor Bertucci, Sally Temple, Stephen J Haggarty, Michael Koob, Jeffrey Trimmer, Marla Weetall, Elisabetta Morini

Published in

Science translational medicine. Volume 18. Issue 863. Pages eady6759. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the brain. These disorders, like frontotemporal dementia (FTD-tau), currently lack effective therapies and can occur sporadically or be inherited when associated with MAPT gene mutations. Exon 10 and adjacent introns of the MAPT gene are a hotspot for pathogenic variants, including splicing mutations that enhance exon 10 inclusion and increase 4R tau expression and 4R-specific gain-of-function mutations that generate aggregation-prone tau. For these 4R tauopathies, a targeted messenger RNA (mRNA) splicing approach that promotes exon 10 exclusion may offer therapeutic benefit. We have developed splicing modulator compounds (SMCs) that promote MAPT exon 10 exclusion and demonstrated their efficacy in neurons derived from patients with FTD carrying the tau Pro³⁰¹→Leu (P301L) gain-of-function mutation or the tau Ser³⁰⁵→Asn (S305N) splicing mutation. Treatment with SMC reduced 4R tau expression and decreased the accumulation of hyperphosphorylated tau (pTau) and oligomeric and insoluble tau proteoforms, thereby rescuing tau-associated neuronal toxicity. A lead SMC corrected the 3R/4R splice ratio in vivo and reduced pTau in the brain of a human gene-replacement mouse model expressing the tau Asn²⁷⁹→Lys (N279K) splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish MAPT pre-mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies.

PMID:
42616837
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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