AAV-OTOF replacement rationale for OTOF c.4759A>T (p.Lys1587Ter)

For OTOF c.4759A>T (p.Lys1587Ter), otoferlin gene replacement is a strong mechanism-matched therapeutic direction because this truncating allele is expected to cause loss of function, and current OTOF gene therapy programs are designed to restore otoferlin expression rather than rescue a specific mutant transcript.

ClinVar classifies OTOF c.4759A>T (p.Lys1587Ter) as pathogenic. Preclinical dual-AAV studies restored otoferlin expression and improved auditory phenotypes in DFNB9 mouse models (PMID:30782832; PMID:30509897). Early human clinical experience has now shown hearing restoration signals after OTOF gene delivery in children with DFNB9, including a single-arm trial of AAV1-hOTOF (PMID:38280389), and additional pediatric studies are ongoing (NCT:NCT05788536; NCT:NCT05821959). Because p.Lys1587Ter is a stop-gain allele in a recessive loss-of-function disease, gene augmentation is more directly supported than mutation-specific editing.

The current human evidence remains early, pediatric, and disease-level rather than specific to p.Lys1587Ter. Real-world applicability still depends on confirming biallelic OTOF-mediated disease, cochlear anatomy, residual target-cell viability, and procedural feasibility. Long-term durability, the best age window for treatment, and immunologic constraints on vector re-dosing remain incompletely defined.