Wu Fan, Chen Guisheng, Hu Rui, Liu Peiwen, Lou Jintao, Zhao Wenji, He Zuhong, Sha Suhua, Zheng Yiqing
Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.
Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Walton Research Building, Room 403-E, 39 Sabin Street, Charleston, SC, 29425, USA.
Adv Sci (Weinh). 2025 Jan 7:e2408873. doi: 10.1002/advs.202408873.
Adeno-associated virus (AAV) vectors are a leading platform for gene therapy. Recently, AAV-mediated gene therapy in the inner ear has progressed from laboratory use to clinical trials, but the lower transduction rates in outer hair cells (OHCs) in the organ of Corti and in vestibular hair cells in adult mice still pose a challenge. OHCs are particularly vulnerable to inner ear insults. In this study, we demonstrated that expression of a key AAV receptor (AAVR, Kiaa0319l, or Au040320) in OHCs and vestibular hair cells decreases significantly in mature mice and AAV particles directly interact with AAVR by forming complexes. Consequently, antibody blockage of AAVR significantly inhibits AAV transduction in sensory hair cells in cochlear explants. Moreover, use of AAVR knockout mice confirms inhibition of AAV transduction in sensory hair cells in vivo. Finally, conditional overexpression of AAVR in sensory hair cells of adult mice successfully restores AAV transduction efficiency in OHCs and vestibular hair cells. In conclusion, this strong evidence that AAVR is essential for AAV transduction in sensory hair cells will help to increase the efficacy of future gene therapy in inner ear.
腺相关病毒（AAV）载体是基因治疗的领先平台。最近，内耳中AAV介导的基因治疗已从实验室应用发展到临床试验，但在成年小鼠的柯蒂氏器外毛细胞（OHC）和前庭毛细胞中的转导率较低仍然是一个挑战。OHC对内耳损伤特别敏感。在本研究中，我们证明，在成熟小鼠中，OHC和前庭毛细胞中关键AAV受体（AAVR、Kiaa0319l或Au040320）的表达显著降低，并且AAV颗粒通过形成复合物直接与AAVR相互作用。因此，AAVR的抗体阻断显著抑制了耳蜗外植体中感觉毛细胞的AAV转导。此外，使用AAVR基因敲除小鼠证实了体内感觉毛细胞中AAV转导的抑制。最后，在成年小鼠的感觉毛细胞中条件性过表达AAVR成功恢复了OHC和前庭毛细胞中的AAV转导效率。总之，这一强有力的证据表明AAVR对于感觉毛细胞中的AAV转导至关重要，将有助于提高未来内耳基因治疗的疗效。
