AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

Jieyu Qi, Fangzhi Tan, Liyan Zhang, Ling Lu, Shanzhong Zhang, Yabo Zhai, Yicheng Lu, Xiaoyun Qian, WenXiu Dong, Yinyi Zhou, Ziyu Zhang, Xuehan Yang, Lulu Jiang, Chaorong Yu, Jiancheng Liu, Tian Chen, Lianqiu Wu, Chang Tan, Sijie Sun, Huaien Song, Yilai Shu, Lei Xu, Xia Gao, Huawei Li, Renjie Chai

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness.