A sound vision: <i>MYO7A</i> gene therapy reaches the inner ear

The field of inner ear gene therapy has reached an exciting turning point. With clinical trials for otoferlin (OTOF) gene therapy currently underway across the US, China, the UK and France, we are witnessing the translation of decades of preclinical research into potential treatments for hereditary hearing loss. The announcement of these trials has been compared to the wait for the Rolling Stones to take the stage (Brigande 2024). Beyond OTOF, gene therapy approaches have been tested for more than twenty genes in mouse models of hearing loss, predominantly using recombinant adeno-associated virus (AAV) vectors. The work by Amariutei et al. (2025) represents a significant milestone in this context, successfully expanding this therapeutic repertoire by treating myosin VIIa (MYO7A)-related hearing impairment in the Shaker-1 (Myo7ash1/sh1) mouse model. MYO7A holds the distinction of being the first gene discovered to cause hereditary hearing loss in humans (Weil et al., 1995). Remarkably, pathogenic variants in this gene are responsible for both a syndromic form of hearing loss, Usher syndrome type 1B (USH1B), and recessive and dominant non-syndromic hearing loss. MYO7A variants are clinically relevant because a recent study demonstrated that MYO7A contributes to 1.4% of all deafness cases, at least in Japan (Watanabe et al. 2024). In USH1B, MYO7A pathogenic variants cause not only profound hearing loss, but also progressive vision loss and balance dysfunction. MYO7A encodes myosin VIIa, a motor protein found in the stereocilia of inner ear hair cells that is crucial for both the development and maintenance of the inner ear hair cell bundles. The auditory phenotype of MYO7A variants varies depending on the mutation's nature and impact on protein stability. In Myo7ash1/sh1 mice, a point mutation at a poorly conserved site leads to normal hair bundle development, followed by subsequent degeneration and early-onset hearing loss; this mutation is analogous to the variants in USH1B. By contrast, mutations causing complete or near-complete absence of Myo7a, such as Myo7a4626SB/4626SB, result in early defective hair bundle development and profound deafness. Earlier attempts to rescue hearing in the Myo7a4626SB/4626SB mice failed to produce detectable hearing improvement (Lau et al. 2023). The study by Amariutei et al. (2025) marks the first successful rescue of hearing in a mouse model of congenital MYO7A hearing loss, representing a crucial step forward in addressing DFNA11, DFNB2 and the auditory component of USH1B. Amariutei et al. (2025) employed a dual AAV vector approach, used previously for Myo7a and other large genes, because the coding sequence is too large for a single AAV vector. The cDNA sequence was split across two AAV backbones, with splice-donor and splice-acceptor sequences incorporated at the 3′ and 5′ ends, respectively, to facilitate splicing-mediated reconstruction of full-length mRNA in vivo. The researchers tested both AAV8 and AAV9-PhP.eB capsids for delivery, finding similar transduction efficiency in inner ear hair cells. The treatment demonstrated several key improvements, including structural and functional recovery of hair cells, as well as a modest improvement in hearing. Scanning electron microscopy revealed restoration of hair bundle structure, with treated mice showing improved morphology, characterized by increased numbers of inner hair cells with multiple rows of stereocilia. The study demonstrated rescue of mechanotransduction currents, albeit at reduced amplitude compared to wild-type controls, and restoration of resting opening probability of mechanotransduction channels, indicating functional recovery at the hair cell level. Finally, auditory brainstem response testing showed a modest but significant 20–30 dB improvement compared to untreated mice. The extent of rescue could probably be enhanced through future innovations in gene delivery, as demonstrated with other deafness genes such as TMC1. The failure of previous attempts to rescue hearing in nonsense-mutation models, combined with limited success in treating mutations affecting early stereocilia development, highlights the narrow therapeutic window for intervention. Once extensive hair cell structural damage occurs, recovery potential becomes severely restricted. In humans, the auditory system becomes functional during embryonic development, with evidence suggesting fetal hearing begins during the second trimester of pregnancy. This timeline suggests that early postnatal intervention may be insufficient for humans with MYO7A mutations, potentially necessitating in utero interventions despite their inherent complexities and ethical considerations. The inner ear encompasses not only the cochlea, responsible for hearing, but also vestibular organs that detect linear and angular head accelerations, which are crucial for balance. Myosin VIIa is important for vestibular hair cell development, and Shaker-1 mice exhibit abnormal balance and circling behaviour. Future studies should assess whether gene therapy rescues vestibular function, in addition to hearing. Additionally, because some deafness genes affect central auditory system components, such as the auditory cortex, comprehensive evaluation through behavioral assays will be essential to determine whether the observed physiological recovery translates to meaningful hearing improvement. This work represents a significant advancement in Myo7a gene therapy, successfully demonstrating hearing rescue in a challenging mouse model. Although therapeutic outcomes show promise, optimizing delivery methods and addressing the critical timing of intervention remain key challenges for clinical translation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. S.T. and K.B.A. wrote the perspective. Breakthrough Award, 2711/22 of the Israel Science Foundation: Karen B. Avraham. ORION Program for Physician-Scientists, Tel Aviv Sourasky Medical Center: Shahar Taiber.