Researchers at Mass Eye and Ear, a division of Mass General Brigham, co-led a recent study that showed how successful gene therapy may be in helping deaf youngsters regain their ability to hear. Researchers found that the novel gene therapy was effective for patients with DFNB9, a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene. The trial involved six children and was conducted at the Eye & ENT Hospital of Fudan University in Shanghai, China. This study is the first human clinical trial to treat this illness with gene therapy, having treated the most patients and had the longest follow-up to date, with the first patient treated in December 2022. Their findings are released in The Lancet.
If children are unable to hear, their brains can develop abnormally without intervention.
The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.
Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School.
Around 26 million people worldwide suffer from congenital deafness, accounting for over 1.5 billion cases of hearing loss. More than 60% of childhood hearing loss cases are hereditary. For instance, the genetic condition DFNB9 is brought on by mutations in the OTOF gene and an inability to create the functional otoferlin protein, which is required for the brain to receive sound impulses from the ear. Since there aren’t any FDA-approved medications to treat congenital deafness, novel approaches like gene treatments are now possible.
Six children with DFNB9 were studied for 26 weeks at the Eye & ENT Hospital of Fudan University to evaluate this experimental therapy. Through a unique surgical approach, the Mass Eye and Ear colleagues carefully inserted a variant of the human OTOF gene into the inner ears of the patients using an adeno-associated virus (AAV). The viral vector was injected once but at different dosages.
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An average auditory brainstem response (ABR) threshold of more than 95 dB was used to diagnose complete deafness in all six research participants. Five children showed signs of hearing recovery after 26 weeks, including a 40–57 decibel drop in ABR tests, significant improvements in speech perception, and the return of their ability to carry on a regular conversation. Overall, there was no evidence of dose-limiting harm. 48 adverse events were noted throughout the patients’ follow-up; the vast majority (96%) of these were low-grade, and the remaining occurrences were transient with no lasting effects.
Evidence for the safety and efficacy of gene therapies in the treatment of DFNB9, as well as its potential for other hereditary hearing loss types, is shown in this article. Furthermore, the findings advance knowledge on the safety of AAV implantation into human inner ears. Regarding AAV use, a dual-AAV vector that carries two copies of the OTOF gene is noteworthy for its success. Since AAVs traditionally have a gene size restriction, the success with a dual viral vector offers the possibility of using AAVs with other large genes that are normally too big for the vector, such as OTOF, which has a gene size limit exceeding that limit.
We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in animal model of DFNB9 to hearing restoration in children with DFNB9.
I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.
Lead study author Yilai Shu, MD, of the Eye & ENT Hospital of Fudan University at Fudan University.
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Not since cochlear implants were invented 60 years ago, has there been an effective treatment for deafness.
This is a huge milestone that symbolizes a new era in the fight against all types of hearing loss.
Zheng-Yi Chen
Source: Mass Eye and Ear – News
Journal Reference: Jun Lv, Hui Wang, Xiaoting Cheng, Yuxin Chen, Daqi Wang, Longlong Zhang, Qi Cao, Honghai Tang, Shaowei Hu, Kaiyu Gao, Mengzhao Xun, Jinghan Wang, Zijing Wang, Biyun Zhu, Chong Cui, Ziwen Gao, Luo Guo, Sha Yu, Luoying Jiang, Yanbo Yin, Jiajia Zhang, Bing Chen, Wuqing Wang, Renjie Chai, Zheng-Yi Chen, Huawei Li, Yilai Shu. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. The Lancet, 2024; DOI: 10.1016/S0140-6736(23)02874-X.
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