OTOF-Related Gene Therapy: A New Way but a Long Road Ahead

Gene therapy for hearing disorders is a promising advancement in the treatment of genetic hearing loss, particularly OTOF-related deafness. Mutations in OTOF disrupt synaptic transmission in cochlear inner hair cells, leading to profound congenital deafness and being a major cause of autosomal recessive non-syndromic auditory neuropathy (DFNB9). For individuals affected, cochlear implants restore partial hearing but cannot fully replicate natural hearing, with limitations in sound quality and speech recognition, especially in noisy environments.

Gene therapy addresses the root cause of OTOF-related deafness. Proof of concept for OTOF gene therapy was shown in two independent animal studies in 2019.1,2 By 2024, clinical studies had shown that delivering a functional OTOF gene via adeno-associated virus (AAV) can partially restore auditory function,3,4 offering promise for near-physiological hearing recovery with a single intervention. This therapy represents a transformative opportunity for patients with DFNB9, especially children, in whom early auditory intervention is crucial for optimal language and cognitive development.

However, OTOF gene therapy faces substantial technical and clinical challenges. The large size of the OTOF gene requires innovative delivery strategies, such as dual-vector systems, which could pose risks of inconsistent gene expression and integration. Key issues, such as the dose, vector proportion, expression efficiency, and long-term safety, remain experimental and require optimisation. Additionally, immune responses to AAV-OTOF could lead to inflammation and damage to the cochlea, posing health risks. Precise delivery and optimum dosage are difficult due to the complex structure of the cochlea. As clinical trials progress, it is clear that an optimal therapeutic protocol of AAV-OTOF requires more than achieving transgene expression in hair cells. Additional human factors need to be considered in evaluating the efficacy.

One key factor is patient age. Animal studies show younger subjects have greater auditory recovery potential.5 Human candidates for OTOF gene therapy are typically infants and young children, as they probably have greater developmental plasticity and less pronounced immune responses to viral vectors, reducing the risk of inflammation or cochlear damage. In our recent multicentre trial (NCT05901480), an adolescent aged 23·9 years showed promising results. After AAV-OTOF injection, the click-evoked auditory brainstem response (ABR), average tune-burst ABR and behavioural hearing threshold was 40 dB, 63 dB, and 63 dB after 9 months, respectively, compared with thresholds of >100 dB, >100 dB, and 101 dB before gene therapy. This result suggests that even adult patients with OTOF-related deafness can also benefit from gene therapy. Gene therapy could provide more natural hearing than cochlear implants, potentially offering faster functional benefits for older patients.

Moving forward, OTOF gene therapy should focus on overcoming technical challenges and optimising therapeutic timing. Research must prioritise the enhancement of gene delivery techniques, such as optimised dual-vector systems or compact mini-gene constructs, to ensure stable and efficient transgene expression. Preclinical research needs to establish the timing of or the optimal therapeutic window for maximum efficacy. Treating patients at various ages will not only identify the optimum timing but also increase understanding of age-related interactions between auditory development and treatment efficacy. Finally, longitudinal studies tracking post-therapy safety and efficacy are needed to ascertain the longevity of the OTOF gene therapy and its overall benefits.

RC declares grants from the National Key Research and Development Program of China (2021YFA1101300, 2021YFA1101800 and 2020YFA0112503), the National Natural Science Foundation of China (82330033, 82030029, 92149304, 82000984), the Natural Science Foundation of Jiangsu Province (BK20232007), the Shenzhen Science and Technology Program (JCYJ20210324125608022), and the 2022 Open Project Fund of Guangdong Academy of Medical Sciences (YKY-KF202201); is Chair of the Association of Hearing, Speech and Communication in Biophysical Society of China; is Vice Chair of the Specialized Committee on Stem Cell Physiology in Chinese Association for Physiological Sciences; is Candidate Chair of the Stem Cell Physiology Committee of Chinese Physiological Society; is Vice Chair of the Developmental biology branch in Chinese Society for Cell Biology; is Vice Chair of the Branch of Stem Cell Engineering Technology, Chinese Society of Biomedical Engineering; holds a technical service contract from Otovia Therapeutics; and is a stockholder of Otovia Therapeutics. JQ declares grants from the National Key Research and Development Program of China (2020YFA0113600), the National Natural Science Foundation of China (82371162, U23A200440), the Natural Science Foundation of Beijing Municipality (7252089), Taishan Scholars Project-Young Experts Program of Shandong Province (tsqn202408320), the Shandong Province Outstanding Youth Science Foundation (ZR2024YQ049), and the STI2030-Major Projects (2022ZD0205400); and is a stockholder of Otovia Therapeutics. LX declares grants from the National Natural Science Foundation of China (82071053) and Taishan Scholars Project-Young Experts Program of Shandong Province (tsqn202211357). F-GZ declares no competing interests.

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