Isgrig Kevin, Ishibashi Yasuko, Lee Hyun Jae, Zhu Jianliang, Grati Mhamed, Bennett Jean, Griffith Andrew J, Roux Isabelle, Chien Wade W
Inner Ear Gene Therapy Program, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, USA.
Otolaryngology Branch, NIDCD, National Institutes of Health, Bethesda, MD, USA.
Mol Ther Methods Clin Dev. 2022 Jul 31;26:371-383. doi: 10.1016/j.omtm.2022.07.013. eCollection 2022 Sep 8.
Inner ear gene therapy using adeno-associated viruses (AAVs) has been successfully applied to several mouse models of hereditary hearing loss to improve their auditory function. While most inner ear gene therapy studies have focused on the mechanosensory hair cells and supporting cells in the organ of Corti, the cochlear lateral wall and the endolymphatic sac have not garnered much attention. The cochlear lateral wall and the endolymphatic sac play critical roles in inner ear ionic and fluid homeostasis. Mutations in genes expressed in the cochlear lateral wall and the endolymphatic sac are present in a large percentage of patients with hereditary hearing loss. In this study, we examine the transduction patterns and efficiencies of conventional (AAV2 and AAV8) and synthetic (AAV2.7m8, AAV8BP2, and Anc80L65) AAVs in the mouse inner ear. We found that AAV8BP2 and AAV8 are capable of transducing the marginal cells and intermediate cells in the stria vascularis. These two AAVs can also transduce the epithelial cells of the endolymphatic sac. Our data suggest that AAV8BP2 and AAV8 are highly useful viral vectors for gene therapy studies targeting the cochlear lateral wall and the endolymphatic sac.
使用腺相关病毒（AAV）的内耳基因疗法已成功应用于多种遗传性听力损失小鼠模型，以改善其听觉功能。虽然大多数内耳基因治疗研究都集中在柯蒂氏器中的机械感觉毛细胞和支持细胞上，但耳蜗外侧壁和内淋巴囊并未受到太多关注。耳蜗外侧壁和内淋巴囊在内耳离子和液体稳态中起关键作用。在很大比例的遗传性听力损失患者中，耳蜗外侧壁和内淋巴囊中表达的基因存在突变。在本研究中，我们研究了传统型（AAV2和AAV8）和合成型（AAV2.7m8、AAV8BP2和Anc80L65）AAV在小鼠内耳中的转导模式和效率。我们发现AAV8BP2和AAV8能够转导血管纹中的边缘细胞和中间细胞。这两种AAV还可以转导内淋巴囊的上皮细胞。我们的数据表明，AAV8BP2和AAV8是针对耳蜗外侧壁和内淋巴囊的基因治疗研究中非常有用的病毒载体。
