The Immune Privilege of the Inner Ear Opens the Way: OTOF Gene Therapy Overcomes Congenital Deafness with Sequential Bilateral Administration
Background
Biallelic mutations in the otoferlin (OTOF) gene cause autosomal recessive deafness type 9 (DFNB9). This protein, essential for synaptic vesicle release in inner hair cells, is deficient, preventing sound signals from being transmitted to the auditory nerve despite a normal cochlear structure. Hearing aids do not provide a fundamental solution, and cochlear implants were the only option, but they do not restore natural hearing.
Gene therapy using adeno-associated virus (AAV) vectors began to enter clinical trials in 2023. However, after administering AAV to one ear, the formation of neutralizing antibodies (NAb) in the body remained a key issue: whether the same vector could be re-administered to the other ear. This is because bilateral hearing recovery is necessary for sound localization and speech discrimination in noisy environments.
Key Findings
A commentary by Nicola Strenzke, published in Nature Medicine in July 2026, highlights the results of two large-scale clinical trials.
Jiang L et al. published a multi-center clinical trial in Nature, in which 42 patients with DFNB9, aged 0.8 to 32.3 years, were administered AAV1-hOTOF and followed up for up to 2.5 years. The auditory brainstem response (ABR) threshold improved continuously from >97 dB before administration to 54 dB at 1 year and 42 dB at 2.5 years. Behavioral audiometry thresholds also recovered from >96 dB to 37 dB, and 90% of participants experienced hearing recovery. The 0.5-18 year age group showed a better response than adults, and patients with a higher number of distortion product otoacoustic emission (DPOAE) at baseline and non-truncated OTOF mutations had better prognoses.
Fan X et al. published a single-arm trial in the same issue of Nature Medicine, taking it one step further. They re-administered the same vector to the other ear of 4 patients aged 2.2 to 3.4 years who had already received AAV1-hOTOF in one ear and had NAb titers of 1:135 to 1:3,645. After 26 weeks, the ABR threshold in the second ear improved to 43-80 dB, and no dose-limiting toxicity was observed. Most adverse events were grade 1 or 2, and no serious adverse events were reported except for one case of grade 3 neutropenia. The fact that the inner ear is an immune-privileged environment, isolated from systemic immune responses by the blood-labyrinth barrier, was the key to the success of the re-administration.
Significance and Prospects
These results show that one of the biggest challenges of AAV-based gene therapy, the re-administration problem, can be solved thanks to the unique anatomical conditions of the inner ear. Unlike systemic diseases such as hemophilia or muscular dystrophy, which require systemic administration, local injection into the inner ear is not significantly affected by pre-existing NAbs.
However, there are still challenges to be addressed. Currently, re-administration data are only available for 4 patients, and patients with high NAb titers showed a slightly lower response. The difference in efficacy in adult patients, the optimal timing and dose, and long-term safety beyond 2.5 years also need to be confirmed. As competing pipelines such as DB-OTO (CHORD study) and SENS-501 report clinical data in NEJM and Molecular Therapy Advances, respectively, the field of DFNB9 gene therapy is rapidly diversifying.
The 90% hearing recovery rate in the 42-patient multi-center trial, and the demonstration of the safety of sequential bilateral administration, indicate that congenital deafness gene therapy is at a turning point, moving beyond the proof-of-concept stage to become a standard treatment.
Nature Medicine, Published online: 09 July 2026; doi:10.1038/s41591-026-04512-5The immune-privileged environment of the inner ear permits sequential bilateral gene therapy for one form of congenital deafness, which adds to growing evidence of the feasibility, safety and efficacy of this innovative curative treatment.
DFNB9 accounts for approximately 2-8% of congenital sensorineural hearing loss. If sequential bilateral gene therapy can be applied to infants and young children with OTOF mutations identified in newborn hearing screening, natural hearing can be restored bilaterally without cochlear implants. This is clinically significant because it prevents the critical period for language development from being missed.
Industrially, the AAV inner ear delivery platform can be expanded to other hearing loss genes such as GJB2 and SLC26A4, beyond OTOF. The confirmation of the possibility of re-administration in an immune-privileged environment also makes it possible to design a dose-escalation re-administration strategy for patients with insufficient efficacy after the first administration. From a regulatory perspective, the standardization of the sequential bilateral administration protocol and the development of companion diagnostics, including NAb monitoring, will be key to commercialization.