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Transl. Med."],"published-print":{"date-parts":[[2026,8,19]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                    gene mutations. Exon 10 and adjacent introns of the\n                    <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                    exon 10 exclusion and demonstrated their efficacy in neurons derived from patients with FTD carrying the tau Pro\n                    <jats:sup>301<\/jats:sup>\n                    \u2192Leu (P301L) gain-of-function mutation or the tau Ser\n                    <jats:sup>305<\/jats:sup>\n                    \u2192Asn (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 Asn\n                    <jats:sup>279<\/jats:sup>\n                    \u2192Lys (N279K) splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish\n                    <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                    pre-mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ady6759","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:59:03Z","timestamp":1787162343000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["<i>MAPT<\/i>\n                    splicing modulators reduce 4R tau and rescue tauopathy phenotypes in human neurons and in a mouse model"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6046-9033","authenticated-orcid":true,"given":"M. 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