Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, 87 Xiangya Road, 410008, Changsha, Hunan, China.
Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA.
Nat Commun. 2021 Jan 29;12(1):697. doi: 10.1038/s41467-020-20808-7.
Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1 mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.
电压门控钾通道 KCNE1 突变导致杰弗里斯和兰尼内尔森综合征 2 型（JLNS2），导致先天性耳聋和前庭功能障碍。我们通过经耳道造口术注射病毒载体进行基因治疗，以治疗 Kcne1 小鼠的听力和前庭症状。结果表明，早期治疗可防止 Reissner 膜和前庭壁塌陷，保持半规管的正常大小，并防止内耳细胞退化。以剂量依赖性方式，至少治疗五个月的高剂量治疗保留了听觉（20 只小鼠中的 16 只）和前庭（20/20）功能。在低剂量组中，只有一小部分（13/20）的小鼠在前庭功能方面有所改善。结果表明，高效转导是实现疗效和维持长期治疗效果的关键因素之一。治疗的次要结果包括提高了出生和窝产存活率。我们的结果表明，通过经耳道造口术进行基因治疗，这种方法被认为是人类内耳基因治疗更可行的递送方法之一，在 JLNS2 小鼠模型中以剂量依赖性方式保留了听觉和前庭功能。
