Molecular Therapy: Methods & Clinical Development (Dec 2023)
Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates
- Longlong Zhang,
- Hui Wang,
- Mengzhao Xun,
- Honghai Tang,
- Jinghan Wang,
- Jun Lv,
- Biyun Zhu,
- Yuxin Chen,
- Daqi Wang,
- Shaowei Hu,
- Ziwen Gao,
- Jianping Liu,
- Zheng-Yi Chen,
- Bing Chen,
- Huawei Li,
- Yilai Shu
Affiliations
- Longlong Zhang
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Hui Wang
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Mengzhao Xun
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Honghai Tang
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Jinghan Wang
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Jun Lv
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Biyun Zhu
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Yuxin Chen
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Daqi Wang
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Shaowei Hu
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Ziwen Gao
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Jianping Liu
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
- Zheng-Yi Chen
- 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 02115, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear, 243 Charles Street, Boston, MA 02114, USA
- Bing Chen
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Corresponding author: Bing Chen, ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
- Huawei Li
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Corresponding author: Huawei Li, ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
- Yilai Shu
- ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Corresponding author: Yilai Shu, ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
- Journal volume & issue
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Vol. 31
p. 101154
Abstract
Pathogenic mutations in the OTOF gene cause autosomal recessive hearing loss (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed an OTOF gene therapy agent by dual-adeno-associated virus 1 (AAV1) carrying human OTOF coding sequences with the expression driven by the hair cell–specific promoter Myo15, AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models using pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing in Otof −/− mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea, although it was detected in other organs such as the CNS and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety of Myo15 promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear of Macaca fascicularis via the round window membrane. AAV1-GFP transduced 60%–94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation.
