ASO-mediated MAPT exon 10 splicing correction for c.2091+16C>T: reducing 4R-tau to rebalance tau isoform ratio

For MAPT c.2091+16C>T, an intronic variant within the exon 10 splice regulatory region that increases exon 10 inclusion and shifts the tau isoform ratio toward pathogenic 4R-tau, antisense oligonucleotide (ASO)-mediated correction of exon 10 splicing represents a mechanistically precise therapeutic strategy. Unlike total MAPT knockdown approaches, splice-switching ASOs targeting the exon 10 regulatory region can specifically reduce 4R-tau while preserving 3R-tau, directly addressing the pathogenic 4R/3R imbalance that drives tau aggregation in FTDP-17 and related tauopathies. This variant sits in the stem-loop structure downstream of the exon 10 5-prime splice site, where C>T destabilizes the RNA secondary structure and enhances U1 snRNP access, increasing exon 10 inclusion.

MAPT c.2091+16C>T is classified as Pathogenic in ClinVar and is one of the well-characterized intronic MAPT mutations that cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The mutation destabilizes the stem-loop structure at the exon 10-intron 10 junction, enhancing exon 10 inclusion and selectively increasing 4R-tau isoforms (Hutton et al., Nature 1998; PMID:9641683). Excess 4R-tau drives neurofibrillary tangle formation preferentially in frontal and temporal cortex. ASO approaches targeting MAPT exon 10 splicing have shown preclinical efficacy: Schoch et al. (J Exp Med 2016; PMID:27185854) demonstrated that intracerebroventricular ASOs can reduce tau protein in prion-tau transgenic mice and prevent tau pathology. Multiple pharmaceutical programs are developing MAPT-targeting ASOs, with Ionis BIIB080 (IONIS-MAPTRx) showing dose-dependent CSF tau reduction in Phase 1b (PMID:36440758). While BIIB080 targets total MAPT rather than exon 10 splicing specifically, the principle of ASO-mediated tau modulation in human CNS is established.

Current clinical MAPT ASOs (BIIB080) reduce total tau rather than specifically correcting the 4R/3R ratio — this is a broader knockdown that also reduces physiologically important 3R-tau. Exon 10 splice-switching ASOs that specifically reduce 4R while preserving 3R would be theoretically superior for splicing mutations like c.2091+16C>T, but such splice-switching ASOs have not yet entered clinical trials. The therapeutic window for FTDP-17 is uncertain: tau pathology may be self-propagating once seeded, potentially limiting benefit of late-stage intervention. Whether reducing 4R-tau production can clear existing neurofibrillary tangles or only prevent new ones is unknown. Intrathecal ASO delivery faces the same repeated-administration burden as other CNS ASO programs. Presymptomatic treatment in MAPT mutation carriers may be necessary for meaningful disease modification, but identifying the optimal biomarker-defined intervention point remains an active research question. CSF p-tau217 and plasma p-tau may serve as pharmacodynamic biomarkers but are less validated for MAPT-FTDP-17 than for Alzheimer disease.