Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2

• Type of Material: Article
• Authors: Xuewen Wu, Emory University; Li Zhang, Emory University; Yihui Li, Changsha Hospital of Traditional Medicine; Wenjuan Zhang, Huazhong University; Jianjun Wang, Emory University; Cuiyun Cai, Central South University; Xi Lin, Emory University
• Language: English
• Date: 2021-01-29
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-20808-7
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 12
• Issue: 1
• Start Page: 697
• End Page: 697
• Grant/Funding Information: This study was supported by a grant to X.L. from the National Institute on Deafness and other Communication Disorders (RO1 DC014496).
• Keywords: DEAFNESS; Science & Technology; Science & Technology - Other Topics; BALANCE; Multidisciplinary Sciences; HEARING; INNER-EAR; DELIVERY; DISORDERS
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

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.