OTOF augmentation logic for c.1498C>T (p.Arg500Ter)

For OTOF c.1498C>T (p.Arg500Ter), otoferlin gene augmentation remains the strongest mechanism-matched therapeutic direction because this early nonsense variant is expected to eliminate normal otoferlin function in a recessive loss-of-function disorder, and current OTOF programs are designed to restore a functional coding sequence rather than repair the specific stop codon.

ClinVar classifies OTOF c.1498C>T (p.Arg500Ter) as pathogenic. Preclinical dual-AAV studies restored otoferlin expression and improved auditory phenotypes in DFNB9 mouse models (PMID:30782832; PMID:30509897). Early human clinical data have now shown hearing restoration signals after OTOF cochlear gene transfer in children, including AAV1-hOTOF experience (PMID:38280389), with additional studies ongoing (NCT:NCT05788536; NCT:NCT05821959). Because p.Arg500Ter is a stop-gain allele in a biallelic loss-of-function deafness gene, replacement is more directly supported than variant-specific editing.

The available human evidence remains early-phase and disease-level rather than specific to p.Arg500Ter. Real-world interpretation still depends on confirming biallelic OTOF-mediated disease, cochlear target-cell viability, surgical timing, and durability of benefit. The best age window and the limits on re-dosing remain open questions.