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

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 <i>MAPT</i> gene mutations. Exon 10 and adjacent introns of the <i>MAPT</i> 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 <i>MAPT</i> 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 <i>MAPT</i> pre-mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies.