Summary: A recent clinical trial demonstrates that gene therapy can restore meaningful hearing in both children and adults who were born deaf or severely hearing-impaired due to mutations in the OTOF gene. Using a synthetic adeno-associated virus to deliver a healthy OTOF copy directly to the inner ear, all ten participants showed measurable hearing gains within one month, with larger improvements observed during 6–12 months of follow-up.
Young children showed the strongest responses: notably, a seven-year-old regained near-normal hearing and conversational ability. Overall the procedure was well tolerated and produced no serious adverse events during the reported follow-up period.
Key Facts:
- Targeted gene: The therapy supplies a functional OTOF gene, addressing otoferlin deficiency that causes auditory signal transmission failure.
- Rapid response: Most participants showed measurable hearing recovery within one month of treatment.
- Safety profile: No serious adverse events reported in the initial 6–12 months; the most common finding was a temporary decrease in neutrophil count.
Source: Karolinska Institute
Overview
Researchers at Karolinska Institutet, in partnership with hospitals and universities in China, report encouraging results from a single-arm trial of AAV-mediated OTOF gene therapy. Published in Nature Medicine, the study evaluated safety and early effectiveness in ten individuals aged 1.5 to 23.9 years who have autosomal recessive deafness due to OTOF mutations.
Maoli Duan, consultant and docent at the Department of Clinical Science, Intervention and Technology at Karolinska Institutet and a corresponding author, describes the results as a major advance in genetic therapies for deafness, with the potential to substantially change life prospects for affected children and adults.
Trial design and delivery method
The investigational treatment uses an engineered adeno-associated virus (Anc80L65 capsid) to carry a working copy of OTOF. Clinicians administered the vector through a single injection into the inner ear via the round window membrane at the base of the cochlea. The trial was carried out at five clinical sites in China and tracked safety and auditory function over time.
Hearing improvement and timeline
Hearing recovery began quickly: most participants regained detectable hearing within one month, and larger gains were recorded at later follow-ups. Across the cohort, the average pure-tone average (PTA) threshold improved from a baseline of 106 ± 9 dB to 52 ± 30 dB at six months. Secondary measures—click-evoked ABR, tone-burst ABR and auditory steady-state responses—showed similar directional improvements.
Stronger effects in younger patients
Age influenced outcomes. Children between five and eight years old experienced the best functional recovery. One seven-year-old regained almost all hearing and could hold everyday conversations with family four months after treatment. Nevertheless, measurable benefits were also seen in older participants, demonstrating that the approach can be effective beyond early childhood.
Safety and tolerability
Safety was a primary endpoint. Over 6–12 months of observation, the therapy was generally well tolerated. Investigators recorded 162 mostly mild-to-moderate (grade I/II) adverse events; the most common laboratory change was a reduced neutrophil percentage in some patients. No serious adverse reactions were reported during the follow-up interval included in this initial report.
The authors emphasize that longer-term monitoring is required to fully establish durability and long-term safety, and the trial remains ongoing to meet the planned extended follow-up period.
Broader implications
Investigators view OTOF as a proof of principle. Teams are expanding efforts toward gene therapies for other genetic causes of deafness—such as GJB2 and TMC1—which are more complex but have shown promise in preclinical animal studies. The study’s success suggests a path forward for developing genetic treatments tailored to different forms of hereditary hearing loss.
Funding and disclosures
The trial was a collaborative effort involving several Chinese institutions, including Zhongda Hospital, Southeast University. Funding came from multiple Chinese research programs and Otovia Therapeutics Inc., the company that developed the gene therapy and employs several investigators. The published paper lists full conflict-of-interest disclosures.
About this genetics and deafness research news
Author: Press Office
Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: Image credited to Neuroscience News
Original Research: Closed access. “AAV gene therapy for autosomal recessive deafness 9: a single-arm trial” by Maoli Duan et al. Nature Medicine
Abstract
AAV gene therapy for autosomal recessive deafness 9: a single-arm trial
Gene therapy for congenital deafness has delivered promising outcomes in children, but data in older individuals have been limited. In this single-arm trial, investigators administered Anc80L65 AAV-OTOF gene therapy to ten participants with autosomal recessive deafness 9, aged 1.5–23.9 years, across five sites in China.
Primary endpoints focus on safety and tolerability over up to five years, with auditory function as a key secondary endpoint. Initial results from the ten participants with 6–12 months of follow-up (one patient received two injections) indicate the treatment was well tolerated, with 162 mainly mild-to-moderate adverse events; decreased neutrophil percentage was the most frequent laboratory finding.
All participants improved their pure-tone average from 106 ± 9 dB at baseline to 52 ± 30 dB. Parallel improvements appeared across other auditory measures: click ABR threshold, tone-burst ABR threshold and auditory steady-state response.
Post hoc analyses showed a rapid onset of benefit, with most hearing improvement evident by one month. Click and tone-burst ABR thresholds predicted behavioral pure-tone thresholds after four months more reliably than auditory steady-state responses. An age-dependent effect favored optimal outcomes in children aged five to eight years. These preliminary findings support the safety and short-term efficacy of AAV-OTOF across a range of ages, while underscoring the need for longer follow-up to confirm durability and long-term safety.
ClinicalTrials.gov registration: NCT05901480.