Base Editing (ABE8e) for MAPT c.2392C>T (p.Arg798Trp) in Frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72/MAPT/SOD1

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.