Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, MA 02115, USA; Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA 02114, USA.
Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Mol Ther. 2023 Sep 6;31(9):2796-2810. doi: 10.1016/j.ymthe.2023.05.005. Epub 2023 May 26.
Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3 homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in Tmprss3 mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons. This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness. It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.
携带有 TMPRSS3 基因突变的患者患有常染色体隐性遗传性耳聋 DFNB8/DFNB10。对于这些患者来说，人工耳蜗植入是唯一的治疗选择。但一些患者的人工耳蜗植入效果并不理想。为了针对 TMPRSS3 患者开展生物治疗，我们构建了一个携带常见的人类 DFNB8 TMPRSS3 突变的敲入小鼠模型。TMPRSS3 纯合子小鼠表现出类似于人类 DFNB8 患者的迟发性进行性听力损失。我们利用 AAV2 作为载体携带人类 TMPRSS3 基因，将 AAV2-hTMPRSS3 注射到成年敲入小鼠内耳，导致毛细胞和螺旋神经节神经元中 TMPRSS3 的表达。在平均年龄为 18.5 个月的 Tmprss3 小鼠中单次注射 AAV2-hTMPRSS3 可使听觉功能持续恢复到类似于野生型小鼠的水平。AAV2-hTMPRSS3 递呈可挽救毛细胞和螺旋神经节神经元。本研究在人类遗传性耳聋的老年小鼠模型中成功实施了基因治疗。它为开发 AAV2-hTMPRSS3 基因治疗 DFNB8 患者奠定了基础，无论是作为单独的治疗方法还是与人工耳蜗植入联合应用。
