AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness
Abstract 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,...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-03-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202306788 |
| _version_ | 1797254983249297408 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jieyu Qi |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T21:58:37Z |
| format | Article |
| id | doaj.art-13ae727fa26b405d86d815a31da8c0fe |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T21:58:37Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-13ae727fa26b405d86d815a31da8c0fe2024-03-20T12:56:12ZengWileyAdvanced Science2198-38442024-03-011111n/an/a10.1002/advs.202306788AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 DeafnessJieyu Qi0Fangzhi Tan1Liyan Zhang2Ling Lu3Shanzhong Zhang4Yabo Zhai5Yicheng Lu6Xiaoyun Qian7WenXiu Dong8Yinyi Zhou9Ziyu Zhang10Xuehan Yang11Lulu Jiang12Chaorong Yu13Jiancheng Liu14Tian Chen15Lianqiu Wu16Chang Tan17Sijie Sun18Huaien Song19Yilai Shu20Lei Xu21Xia Gao22Huawei Li23Renjie Chai24State Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaDepartment of Otolaryngology‐Head and Neck Surgery the Affiliated Drum Tower Hospital of Nanjing University Medical School Jiangsu Provincial Key Medical Discipline (Laboratory) Nanjing 210008 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaSchool of Medicine Southeast University Nanjing 210009 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaDepartment of Otolaryngology‐Head and Neck Surgery the Affiliated Drum Tower Hospital of Nanjing University Medical School Jiangsu Provincial Key Medical Discipline (Laboratory) Nanjing 210008 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaOtovia Therapeutics Inc Suzhou 215101 ChinaFosun Health Capital Shanghai 200233 ChinaENT Institute and Department of Otorhinolaryngology Eye & ENT Hospital State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Fudan University Shanghai 200031 ChinaDepartment of Otolaryngology‐Head and Neck Surgery Shandong Provincial ENT Hospital Shandong University Jinan Shandong 250022 ChinaDepartment of Otolaryngology‐Head and Neck Surgery the Affiliated Drum Tower Hospital of Nanjing University Medical School Jiangsu Provincial Key Medical Discipline (Laboratory) Nanjing 210008 ChinaENT Institute and Department of Otorhinolaryngology Eye & ENT Hospital State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Fudan University Shanghai 200031 ChinaState Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck Surgery Zhongda Hospital School of Life Sciences and Technology School of Medicine Advanced Institute for Life and Health Jiangsu Province High‐Tech Key Laboratory for Bio‐Medical Research Southeast University Nanjing 210096 ChinaAbstract 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.https://doi.org/10.1002/advs.202306788AAVbiosafetyclinical trialhearing recoveryOTOF gene therapy |
| spellingShingle | 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 AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness Advanced Science AAV biosafety clinical trial hearing recovery OTOF gene therapy |
| title | AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness |
| title_full | AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness |
| title_fullStr | AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness |
| title_full_unstemmed | AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness |
| title_short | AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness |
| title_sort | aav mediated gene therapy restores hearing in patients with dfnb9 deafness |
| topic | AAV biosafety clinical trial hearing recovery OTOF gene therapy |
| url | https://doi.org/10.1002/advs.202306788 |
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