Frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72/MAPT/SOD1

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.

Base Editing (ABE8e) via LNP delivery is a rationale-driven therapeutic strategy for Frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72/MAPT/SOD1 targeting the MAPT c.2392C>T (p.Arg798Trp) variant (Pathogenic, missense variant, non-coding transcript variant, intron variant). The editing system (ABE8e-nSpCas9 (adenine base editor)) converts the pathogenic A back to G on the target strand, restoring the wild-type codon. Target tissue: Liver. Therapeutic goal: Correct the MAPT P301L mutation at chr17:46010879 to restore wild-type tau function and prevent or slow frontotemporal dementia within the ALS-FTD spectrum. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Low, immunogenicity Low.

1. Molecular basis: MAPT NM_001377265.1(MAPT):c.2392C>T (p.Arg798Trp) is classified as Pathogenic (ClinVar variation ID 14247). Molecular consequence: missense variant, non-coding transcript variant, intron variant. Protein change: R406W, R723W, R375W, R317W, R346W, R741W, R348W, R377W, R701W, R798W. 2. Epidemiology: Frontotemporal dementia (FTD) is an early-onset dementia with a prevalence of roughly 10–15 per 100,000 and accounts for 5–10% of all dementias, often presenting before age 65 [WEB-01, PAPER-03]. Amyotrophic lateral sclerosis (ALS) has an incidence of about 1–3 per 100,000 person-years and a prevale 3. Standard of care: ALS standard of care combines modestly effective disease-modifying drugs (riluzole and edaravone) and intensive multidisciplinary supportive care, including respiratory and nutritional support; riluzole extends survival by only a few months and edaravone produces small functional benefits in selecte 4. Pipeline: Across the ALS-FTD spectrum, multiple modalities are in development. In ALS, numerous Phase II/III trials of small molecules and repurposed drugs are ongoing (e.g., ZYIL1 Phase II ALSFRS-R–based trial NCT05981040) [WEB-04]. Gene-targeted therapies include ASOs for SOD1 (tofersen, accelerated approva 5. ABE clinical validation: ABE8e (Richter et al. 2020, Nat Biotechnol) achieves ~1.7x higher editing efficiency than ABE7.10. VERVE-101 demonstrated first-in-human LNP-ABE liver editing with 55-66% PCSK9 reduction (Raal et al. 2025, NEJM). Beam Therapeutics is advancing multiple ABE programs.

1. No published data specifically correcting MAPT c.2392C>T (p.Arg798Trp) with Base Editing (ABE8e); strategy is based on general principles and must be validated preclinically. 2. PAM availability and bystander base analysis for the specific genomic context have not been performed. If no canonical NGG PAM positions the target within the editing window, PAM-flexible variants (SpRY) may be needed. 3. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.