MAPT Splicing Modulators as a Therapeutic Strategy for Tauopathies

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Tauopathies are neurodegenerative diseases defined by abnormal tau protein accumulation.
• Current therapies for tauopathies, such as frontotemporal dementia (FTD-Tau), are limited.
• Pathogenic variants in the MAPT gene, particularly affecting exon 10 splicing, drive 4R tauopathies.

Purpose of the Study:

• To discover and characterize novel splicing modulator compounds (SMCs) targeting MAPT pre-mRNA splicing.
• To evaluate the therapeutic efficacy of SMCs in preclinical models of 4R tauopathies.

Main Methods:

• Identification of novel SMCs promoting MAPT exon 10 exclusion.
• Testing SMC efficacy in FTD patient-derived neuronal models with P301L or S305N mutations.
• Assessment of SMC effects on 4R tau expression, tau phosphorylation, and aggregation.
• In vivo validation in a gene-replacement mouse model with the tau-N279K splicing mutation.

Main Results:

• SMCs successfully promoted MAPT exon 10 exclusion.
• Treatment reduced 4R tau expression, hyperphosphorylated tau (pTau), and insoluble tau aggregates.
• SMC treatment rescued tau-associated neuronal toxicity in patient-derived models.
• Lead SMC corrected the 3R/4R splice ratio in vivo and reduced brain pTau in a mouse model.

Conclusions:

• SMC-based modulation of MAPT pre-mRNA splicing is a viable therapeutic strategy for 4R tauopathies.
• These novel compounds demonstrate significant potential for treating neurodegenerative conditions characterized by aberrant tau processing.