OTOF gene therapy for hearing loss: hearing recovery reported in 90% of 42 participants in a single-arm trial, with follow-up up to 2.5 years
Hearing improvement in OTOF-related hearing loss
In a multicenter clinical trial involving 42 patients with autosomal recessive deafness type 9 caused by OTOF variants, hearing recovery was reported in 90% of participants after AAV1-hOTOF gene therapy. Hearing improvement persisted during follow-up of up to 2.5 years, and speech perception gradually improved among participants whose hearing recovered. However, the abstract’s term “hearing recovery” cannot be interpreted as attainment of normal hearing or a cure.
OTOF-related hearing loss is a condition characterized by congenital severe to profound hearing loss. Earlier studies in a small number of patients reported benefits from gene therapy, but safety and efficacy across a broader age range, duration of benefit, and characteristics associated with treatment response had not been adequately established. This study addressed those questions and was published as a full research article in Nature.
Three dose groups evaluated at eight centers
The study was a single-arm clinical trial conducted at eight centers, assessing outcomes in treated participants without a control group. Participants were 0.8–32.3 years old and received AAV1-hOTOF in three dose groups. This adeno-associated virus serotype 1 vector carries the protein-coding sequence of the human OTOF gene.
The primary endpoint was dose-limiting toxicity within six weeks after administration; no such toxicity was observed in the trial. Secondary assessments examined efficacy and adverse events. A decreased neutrophil count was reported as a grade 3 adverse event, so the absence of dose-limiting toxicity should not be taken to mean that there were no severe adverse events. The abstract does not provide details on adverse-event frequency or causal relationships with treatment.
Changes in hearing thresholds and speech perception
Auditory brainstem response testing measures the response of the auditory pathway to sound. Its threshold is the sound intensity needed to detect a response; a lower threshold indicates improved hearing. The thresholds reported in the abstract gradually decreased from more than 97±1 dB nHL before treatment to 54±3 at 1 year, 51±3 at 1.5 years, 50±3 at 2 years, and 42±5 dB nHL at 2.5 years after treatment.
Thresholds also improved on behavioral audiometry, which assesses behavioral responses to sound, from more than 96±3 dB HL before treatment to 37±5 dB HL at 2.5 years. The two tests use different measurement methods and reference standards, so their values are difficult to compare directly. Speech perception gradually improved among participants whose hearing recovered, but the abstract did not provide specific scores.
The follow-up period was “up to 2.5 years.” Because the abstract does not state how many participants were assessed at each time point, it cannot be concluded that every participant was followed for 2.5 years or maintained the same level of benefit. The specific criteria used to define the 90% recovery rate and the statistical meaning of the ± values accompanying the measurements also cannot be determined from the abstract alone.
Characteristics associated with treatment response and remaining questions
Children and adolescents showed greater hearing improvement than adults. Better hearing recovery was also associated with a greater number of test items showing a response on pretreatment distortion-product otoacoustic emission (DPOAE) testing, or with non-truncating variants in both alleles of the OTOF gene. These findings offer clues for examining differences in treatment response, but they do not establish criteria for definitively predicting individual benefit or demonstrate the superiority of early treatment.
The researchers interpreted the findings as showing treatment tolerability across a broader patient age range and sustained benefit for up to 2.5 years. However, this was a study of 42 participants without a control group, and the materials reviewed for this article were the abstract and bibliographic information. Further validation is needed regarding long-term safety, differences in individual response, and benefit compared with existing hearing rehabilitation. The key findings can be found in the abstract and bibliographic information for the Nature article indexed by Europe PMC.
Nature, Published online: 22 April 2026; doi:10.1038/s41586-026-10393-yIn a multicentre trial of AAV1-hOTOF gene therapy involving 42 participants aged 0.8–32.3 years with autosomal recessive deafness 9, treatment demonstrated safety, tolerability, and improved hearing and speech perception, with age and distortion product otoacoustic emissions associated with treatment outcomes.
This study expands observation of gene therapy for OTOF-related hearing loss from a small number of patients to 42 participants at eight centers and evaluates the persistence of hearing improvement for up to 2.5 years. In addition to auditory brainstem responses, it assessed behavioral hearing and speech perception, adding evidence about functional changes. Associations between age, pretreatment DPOAE responses, variant type, and treatment response may help group patients by their characteristics and interpret outcomes in subsequent trials. These findings cannot, however, be established as criteria for selecting patients for treatment or generalized to other forms of hereditary hearing loss. Longer follow-up, comparative studies, and evaluation of effects on everyday communication are needed to judge clinical value.