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These disorders, like frontotemporal dementia (FTD-Tau), currently lack effective therapies and can occur sporadically or be inherited when associated with\n                  <jats:italic>MAPT<\/jats:italic>\n                  gene mutations. The\n                  <jats:italic>MAPT<\/jats:italic>\n                  gene region encompassing exon 10 and adjacent introns is a hotspot for pathogenic variants, including splicing mutations that enhance exon 10 inclusion and increase 4R tau expression, and gain-of-function mutations that generate aggregation-prone mutant 4R tau protein. For these 4R-specific tauopathies, a targeted mRNA splicing approach that promotes exon 10 exclusion may offer therapeutic benefit. In this study, we discovered novel splicing modulator compounds (SMCs) that promote\n                  <jats:italic>MAPT<\/jats:italic>\n                  exon 10 exclusion, and demonstrated their efficacy in FTD patient-derived neuronal models carrying the tau-P301L gain-of-function mutation or the tau-S305N splicing mutation. Treatment with SMC reduced 4R tau expression and decreased the accumulation of hyperphosphorylated tau (pTau), oligomeric and insoluble tau, thereby rescuing tau-associated neuronal toxicity. Importantly, our lead SMC corrected the 3R\/4R splice ratio\n                  <jats:italic>in vivo<\/jats:italic>\n                  and significantly reduced pTau in the brain of a gene- replacement (GR) mouse model expressing the human tau-N279K splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish\n                  <jats:italic>MAPT<\/jats:italic>\n                  pre- mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    Discovery of SMCs that correct\n                    <jats:italic>MAPT<\/jats:italic>\n                    splicing, reduce 4R tau, and rescue pathology in patient- derived neuronal and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models of 4R tauopathies.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.06.652428","type":"posted-content","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T23:35:11Z","timestamp":1746920111000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>MAPT<\/i>\n                  Splicing Modulators as a Therapeutic Strategy for Tauopathies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5421-6673","authenticated-orcid":false,"given":"M. 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