Researchers restore hearing and balance in mice by replacing defective protein; work highlights gene therapy’s potential for certain forms of inherited deafness.
A study from researchers at Tel Aviv University reports that restoring a single protein – CLIC5 – using adeno-associated virus (AAV) vectors can partially rescue both hearing and vestibular function in mice, pointing to a potential treatment path for patients with CLIC5-related deafness.Gene therapy is increasingly being investigated by numerous research teams to treat deafness, but, according to the study authors, “the genetic heterogeneity of hearing loss remains a significant challenge, requiring gene-specific analysis and optimization of current approaches for broader treatment applications.”Focusing on the CLIC5 protein, which is associated with autosomal recessive hearing loss in humans, along with vestibular dysfunction, the team, led by Karen Avraham and Roni Hahn, designed two gene replacement strategies to deliver a healthy copy of Clic5 (the mouse equivalent of human CLIC5) to mutant mice. One used a conventional single-stranded AAV (ssAAV), while the other employed a self-complementary AAV (scAAV), which was engineered to bypass the need for second-strand synthesis and initiate expression more rapidlyBoth approaches restored CLIC5 protein expression in the inner ear and preserved hair cell architecture, though the scAAV approach achieved results comparable to ssAAV while requiring a tenfold lower dose.However, the improvements were not uniform across frequencies. While lower and mid-range hearing was largely rescued, high-frequency thresholds deteriorated over time in treated mice. Vestibular function appeared more stable, with circling behavior and hyperactivity reduced for up to 12 weeks post-treatment. The authors suggest this difference may be linked to the distinct development timelines and protein turnover rates of auditory versus vestibular hair cells. They write: “Limited rescue and durability at high frequencies may result from several factors, including promoter downregulation, an immune response against the viral capsid, the earlier development of the cochlear base compared to other cochlear regions, or the genetic background of the mice.”Because CLIC5-related hearing loss in humans typically emerges during childhood rather than at birth, treatment may be feasible after the onset of hearing but before extensive hair cell damage occurs. The team concludes that: “The ability to use scAAVs for effective treatment addresses current therapeutic gaps and adds to the growing toolbox of gene therapy strategies for a broader range of genetic hearing loss conditions.”The study was conducted in collaboration with Jeffrey Holt and Gwenaëlle Géléoc from Boston Children’s Hospital and Harvard Medical School and was supported by the US-Israel Binational Science Foundation, the National Institutes of Health/NIDCD, and the Israel Science Foundation Breakthrough Research Program.Source
