2020-5-10 figures raw data.zip

Mutations in voltage-gated potassium channel KCNE1 cause Jervell & 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 that the 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 significantly preserved auditory (16 out of 20 mice, or 16/20) 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 high-efficacy 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的突变可引发2型Jervell & Lange-Nielsen综合征（JLNS2），导致先天性耳聋与前庭功能障碍。本研究采用半规管造口术（canalostomy）递送病毒载体的基因疗法，对Kcne1基因敲除（Kcne1-/-）小鼠进行干预，以治疗其听觉与前庭症状。实验结果显示，该疗法可阻止前庭膜（Reissner’s membrane）与前庭壁塌陷，维持半规管的正常形态，并防止内耳细胞变性。该疗法呈剂量依赖效应：高剂量组小鼠的听觉功能（16/20只，即80%）与全部（20/20只）前庭功能至少可维持5个月正常；低剂量组中，亚组小鼠（13/20只）仅前庭功能得到改善。研究证实，高效转导（transduction）是实现治疗效果并维持长期疗效的关键因素之一。该疗法的次要结局指标包括提高小鼠的出生率与产仔存活率。本研究结果表明，通过半规管造口术实施的基因疗法（该方法被认为是人类内耳基因治疗中较为可行的递送方式之一），可在JLNS2小鼠模型中以剂量依赖的方式保留听觉与前庭功能。