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

被引：83

作者：

Qi, Jieyu ^{[1
,2
,3
]}

Tan, Fangzhi ^{[1
]}

Zhang, Liyan ^{[1
]}

Lu, Ling ^{[4
]}

Zhang, Shanzhong ^{[5
]}

Zhai, Yabo ^{[6
]}

Lu, Yicheng ^{[1
]}

Qian, Xiaoyun ^{[4
]}

Dong, Wenxiu ^{[5
]}

Zhou, Yinyi ^{[1
]}

Zhang, Ziyu ^{[1
]}

Yang, Xuehan ^{[1
]}

Jiang, Lulu ^{[5
]}

Yu, Chaorong ^{[5
]}

Liu, Jiancheng ^{[5
]}

Chen, Tian ^{[1
]}

Wu, Lianqiu ^{[5
]}

Tan, Chang ^{[5
]}

Sun, Sijie ^{[5
,7
]}

Song, Huaien ^{[7
]}

Shu, Yilai ^{[8
,9
,10
,11
,12
]}

Xu, Lei ^{[13
]}

Gao, Xia ^{[4
]}

Li, Huawei ^{[8
,9
,10
,11
,12
,14
,15
]}

Chai, Renjie ^{[1
,2
,3
,16
,17
]}

机构：

[1] Southeast Univ, Dept Otolaryngol Head & Neck Surg, State Key Lab Digital Med Engn, Zhongda Hosp,Sch Life Sci & Technol,Adv Inst Life, Nanjing 210096, Peoples R China

[2] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, Peoples R China

[3] Beijing Inst Technol, Aerosp Ctr Hosp, Sch Life Sci, Dept Neurol, Beijing 100081, Peoples R China

[4] Nanjing Univ, Affiliated Drum Tower Hosp, Jiangsu Prov Key Med Discipline Lab, Dept Otolaryngol Head & Neck Surg,Med Sch, Nanjing, Peoples R China

[5] Otovia Therapeut Inc, Suzhou 215101, Peoples R China

[6] Southeast Univ, Sch Med, Nanjing 210009, Peoples R China

[7] Fosun Hlth Capital, Shanghai 200233, Peoples R China

[8] Fudan Univ, ENT Inst, Shanghai 200031, Peoples R China

[9] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China

[10] Fudan Univ, NHC Key Lab Hearing Med, Shanghai 200032, Peoples R China

[11] Fudan Univ, Eye & ENT Hosp, Dept Otorhinolaryngol, State Key Lab Med Neurobiol, Shanghai 200031, Peoples R China

[12] Fudan Univ, MOE Frontiers Ctr Brain Sci, Shanghai 200031, Peoples R China

[13] Shandong Univ, Shandong Prov ENT Hosp, Dept Otolaryngol Head & Neck Surg, Jinan 250022, Shandong, Peoples R China

[14] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China

[15] Fudan Univ, Collaborat Innovat Ctr Brain Sci, Shanghai 200032, Peoples R China

[16] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Otolaryngol Head & Neck Surg, Chengdu 610072, Peoples R China

[17] Southeast Univ, Shenzhen Res Inst, Shenzhen 518063, Peoples R China

来源：

ADVANCED SCIENCE | 2024年 / 11卷 / 11期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

AAV; biosafety; clinical trial; hearing recovery; OTOF gene therapy; MOUSE MODEL; RESCUES HEARING; OTOF MUTATIONS; ENABLES SAFE; OTOFERLIN; OUTCOMES; BALANCE;

D O I：

10.1002/advs.202306788

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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. This study evaluates the efficacy and safety of an adeno-associated virus (AAV) based gene therapy AAV-OTOF in patients with DFNB9 deafness. AAV-OTOF injection can restore the hearing function of the previous deaf ear to a normal level with safety. This proof of concept study provides clinical gene therapy data for DFNB9 deafness and also supplies support for other inner ear gene therapies.image

引用

页数：13