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

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.