Gene Therapy Restored Partial Hearing in a Dozen Deaf Children

Dr. Fan-Gang Zeng is the chairman of The Hearing Journal Editorial Advisory Board, as well as the director of the Center for Hearing Research and a professor of anatomy and neurobiology, biomedical engineering, cognitive sciences, and otolaryngology at the University of California Irvine. On February 3, 2024, five companies from three continents reported the first-in-human results that drugs delivered to the inner ear have restored partial hearing to a dozen deaf children. The results were reported at The 47th Annual Midwinter Meeting of The Association for Research in Otolaryngology in Anaheim, Calif. (www.aro.org). Figure. Dr. Yilai Shu checked on one of the children (No. 4) who received gene therapy. Used with permission from Dr. Shu. One in 500 babies are born deaf or hard of hearing. About 60% of them have some form of gene mutations. Medical devices like cochlear implants are the gold standard treatment, but there is no drug that can treat any deafness until now. All five companies targeted the same gene, OTOF, which is only expressed in the inner hair cells, functioning like microphones to transfer sound information from the inner ear to the auditory nerve. They all used a similar technical approach called adeno-associated virus or AAV-mediated gene therapy to deliver the OTOF gene to the patient’s inner ear. This approach has been verified to be safe and effective in animals before it was used for humans. Yilai Shu from Fudan University, supported by Refreshgene Therapy, reported that in five of the six children (age range = 1-6 y) whose deafness was confirmed due to OTOF mutations, a single injection of the drug into in one ear improved hearing thresholds from profound deafness (~95 dB HL) to moderate hearing loss (40-50 dB HL) at the 26-week follow-up timepoint. Shu also reported similar improvements in one of the five children (10 y), who received the same single-dose injection but in both ears. Excitingly, not only did this child improve the hearing threshold, but also showed signs of restored capabilities in sound localization and speech communication. The results from the six cases with single ear injection were also published in The Lancet on January 24. Otovia reported results from three of the five deaf children (5, 7, and 8 y) who received single injection in one or both ears: In 1-2 months, two of the three had hearing in the normal range while the third one showed only moderate hearing loss (40 dB HL). Anecdotal evidence suggested that these kids could hear and understand speech through the drug-injected ears. Akouos, acquired by Eli Lilly in 2022, showed that 1-2 months after single injection, two children (8 and 11 y) improved their hearing by 40 dB from profound hearing loss to moderate loss. Decibel, acquired by Regeneron in 2023, reported results from a deaf infant (18 m) who simultaneously received a cochlear implant in one ear and single injection of the drug in the other. After 12 weeks, the hearing threshold was improved by 50 dB in the drug-treated ear. Sensorion, the earliest entry to the deaf gene therapy market in 2009, recently enrolled three patients in their clinical trial but did not present any data regarding their performance.Dr. Yilai Shu checked on one of the children (No. 4) who received gene therapy. Used with permission from Dr. Shu.Importantly, the five companies all have followed a similar path to first establish safe, tolerance and efficacy in mice, then in non-human primates, before the clinical trials in humans. The gene drug is also delivered similarly through the round window in the cochlea. Similar to the cochlear implant, antibiotics and steroids are typically prescribed after the surgery. Some adverse events like coughing and infection were reported, but none were deemed related to the gene therapy procedure. While these initial results are exciting and promising, there are caveats. First, the OTOF gene mutation is rare, with about 200,000 patients globally, and less than 50 new cases annually in the US. Second, the present gene therapy has restored audibility, but not necessarily the impaired temporal processing, which is critical to speech and music perception. Third, it is yet to be determined whether the drug-treated ear will outperform the state-of-art treatment for deafness, namely, the cochlear implant. Fourth, it remains to be seen whether the restored hearing stays or deteriorates over time, if latter, will re-dose work or even be possible? Finally, the initial results are already showing a large individual variability in efficacy, making it difficult to determine candidacy and predict outcomes. Although it is too early to predict the full potential of gene therapy, Yuri Agrawal, an ENT physician and President of The Association for Research in Otolaryngology, told a standing-room-only audience that the exciting results from these trials had taken a giant step forward in the drug treatment of deafness. Debara Tucci, Director of the National Institute on Deafness and Other Communication Disorders, also an ENT physician, echoed that gene therapy signals the beginning of a new era for treating deafness and beyond.