Elisabetta Morini, PhD

Tauopathies, devastating neurodegenerative diseases in which tau proteins build up abnormally in the brain, currently lack effective treatments.

Many tauopathies share a common mechanism where abnormal splicing of the MAPT gene (which encodes the tau protein) causes an imbalance between two forms of tau, resulting in an excess of toxic 4R tau.

While most therapeutics have focused on treating downstream consequences—in other words, removing tau after it has already accumulated—Mass General Brigham’s M. Catarina Silva, PhD, and Elisabetta Morini, PhD, took a new approach to target this underlying splicing malfunction.

In their recent study, the researchers developed a new class of small-molecule splicing modulators designed to correct abnormal MAPT splicing and restore a healthier tau balance.

In neurons derived from patients with frontotemporal dementia (a type of tauopathy) carrying MAPT mutations, the compounds reduced 4R tau levels, decreased multiple pathological forms of tau and protected neurons from toxicity.

M. Catarina Silva, PhD

To test whether this approach could work in a living brain and not just in cultured cells, the researchers evaluated a lead compound in a mouse model carrying a human MAPT mutation. Oral treatment improved the ratio of 3R and 4R tau and reduced markers of tau pathology.

The authors note this approach could represent a new therapeutic strategy for a broad range of genetic and sporadic 4R tauopathies.

Published in Science Translational Medicine on August 19, 2026 | Read the paper: “MAPT Splicing Modulators Reduce 4R Tau and Rescue Tauopathy Phenotypes in Human Neurons and in a Gene-Replacement Mouse Model”

Summary reviewed by: M. Catarina Silva, PhD, lead author; Elisabetta Morini, PhD, senior author