Base Editing (ABE8e) for OTOF c.3515G>A (p.Arg1172Gln) in Hereditary sensorineural hearing loss due to OTOF (DFNB9)

Base Editing (ABE8e) via AAV delivery is a rationale-driven therapeutic strategy for Hereditary sensorineural hearing loss due to OTOF (DFNB9) targeting the OTOF c.3515G>A (p.Arg1172Gln) variant (Pathogenic, missense variant, 3 prime UTR 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: Ear. Therapeutic goal: Restore functional OTOF expression in inner hair cell synapses via gene therapy or gene editing to recover auditory neurotransmission and improve hearing.. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: OTOF NM_194323.3(OTOF):c.3515G>A (p.Arg1172Gln) is classified as Pathogenic (ClinVar variation ID 548986). Molecular consequence: missense variant, 3 prime UTR variant. Protein change: R1939Q, R1172Q. 2. Epidemiology: Congenital or early-onset severe-to-profound sensorineural hearing loss with auditory neuropathy phenotype (absent ABR, preserved otoacoustic emissions). OTOF mutations account for a substantial subset of auditory neuropathy spectrum disorder cases in several populations; congenital severe-to-profou 3. Standard of care: Early cochlear implantation is standard for children with OTOF-related auditory neuropathy and can yield speech perception outcomes comparable to other congenital deafness etiologies when performed early. Conventional hearing aids are generally ineffective; lifelong device dependence and rehabilitat 4. Pipeline: An AAV-based dual-vector gene therapy, DB-OTO, is in Phase I/II clinical development with NEJM-reported clinically meaningful hearing and speech improvements after single intracochlear injection in children with OTOF mutations. Additional OTOF-directed approaches, including AAV gene replacement and 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 OTOF c.3515G>A (p.Arg1172Gln) 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.