Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate.
Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate.
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DOI：
10.1002/advs.202306201
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发表时间：
2024-01
期刊：
影响因子：
--
通讯作者：
Chai R
中科院分区：
文献类型：
--
作者：
Qi J;Zhang L;Tan F;Zhang Y;Zhou Y;Zhang Z;Wang H;Yu C;Jiang L;Liu J;Chen T;Wu L;Zhang S;Sun S;Sun S;Lu L;Wang Q;Chai R
OTOF突变是听神经病的主要原因。有关于小鼠Otof相关基因治疗的报道，但没有关于药物评价的临床前研究。在这里，Anc 80 L 65和小鼠毛细胞特异性Myo 15启动子（mMyo 15）用于选择性和有效地将人OTOF递送到小鼠和非人灵长类动物的毛细胞，以评估OTOF基因治疗药物的有效性和安全性。产生了一种新的转移全长OTOF的双-AAV-OTOF-杂交策略，其可以稳定地恢复患有深度耳聋的成年OTOFp.Q939*/Q939* 小鼠的听力，最长持续时间至少为150天，并且治疗效果最好，与野生型小鼠的听力没有差异。进一步建立了无听力障碍食蟹猴耳蜗中的AAV显微注射方法，发现毛细胞中的mMyo 15启动子可以安全有效地驱动OTOF。此外，腺相关病毒药物的治疗剂量对小鼠和非人灵长类动物的正常听力没有影响，也不会引起显着的全身毒性。综上所述，本研究为DFNB 9患者的临床基因治疗提供了一种潜在的策略，为临床研究和应用提供了完整、规范、系统的研究数据。本研究提出了一种基因治疗药物AAV-OTOF，并在小鼠和非人灵长类动物中对AAV-OTOF基因治疗进行了临床前和系统的有效性和安全性评价，同时建立了一种听觉安全的非人灵长类动物内耳AAV递送方法，可用于指导OTOF相关性耳聋DFNB 9的临床研究，为内耳基因治疗提供方法学支持。
OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof‐related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell‐specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual‐AAV‐OTOF‐hybrid strategy to transfer full‐length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild‐type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application. This study proposes a gene therapy drug AAV‐OTOF and provides preclinical and systematic efficacy and safety evaluation for AAV‐OTOF gene therapy both in mice and nonhuman primate, and also establishes a hearing‐safe approach for AAV delivery into the inner ear in nonhuman primate, which can be used to guide the clinical studies of OTOF‐related deafness DFNB9 and provide methodological support for inner ear gene therapies.
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影响因子：
16.6
作者：
Andres-Mateos E;Landegger LD;Unzu C;Phillips J;Lin BM;Dewyer NA;Sanmiguel J;Nicolaou F;Valero MD;Bourdeu KI;Sewell WF;Beiler RJ;McKenna MJ;Stankovic KM;Vandenberghe LH
通讯作者：
Vandenberghe LH
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影响因子：
11.1
作者：
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通讯作者：
Avraham KB
影响因子：
4.2
作者：
Li, Juan;Sun, Wunchang;Liu, Xiang-Qin
通讯作者：
Liu, Xiang-Qin
影响因子：
11.1
作者：
Al-Moyed, Hanan;Cepeda, Andreia P.;Reisinger, Ellen
通讯作者：
Reisinger, Ellen
影响因子：
5.3
作者：
Tang, Honghai;Wang, Hui;Shu, Yilai
通讯作者：
Shu, Yilai