Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results.

Hui Wang, Yilai Shu, Zheng-Yi Chen, Wuqing Wang, Kaiyu Gao, Ziwen Gao, Luo Guo, Yanbo Yin, Luoying Jiang, Chong Cui, Honghai Tang, Mengzhao Xun, Chunxin Xu, Biyun Zhu, Xiaoting Cheng, Sha Yu, Shaowei Hu, Jun Lv, Yi Zhou, Min Shen, Bing Chen, Zijing Wang, Jinghan Wang, Qi Cao, Yuxin Chen, Jiajia Zhang, Longlong Zhang, Lei Han, Daqi Wang, Huawei Li

Journal: Nature medicine 2024;30(7):1898-1904

PMID: 38839897

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Abstract

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .

Address: ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai, China.; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China.; ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai, China.; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China.; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.; ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai, China.; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China.; Department of Otorhinolaryngology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.; Shanghai Rehabilitation Institute for the Exceptional Children, Shanghai, China.; Shanghai Refreshgene Therapeutics Co. Ltd., Shanghai, China.; ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai, China. [email protected].; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China. [email protected].; Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA. [email protected].; Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA, USA. [email protected].; ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai, China. [email protected].; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China. [email protected].; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. [email protected].; ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai, China. [email protected].; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China. [email protected].; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. [email protected].

DOI: 10.1038/s41591-024-03023-5

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MeSH Terms: Humans, Genetic Therapy, Child, Male, Female, Dependovirus, Child, Preschool, Deafness, Adolescent, Treatment Outcome, Genes, Recessive, Genetic Vectors, Evoked Potentials, Auditory, Brain Stem