Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2.
Xuewen Wu, Li Zhang, Yihui Li, Wenjuan Zhang, Jianjun Wang, Cuiyun Cai, Xi Lin
Author Information
Xuewen Wu: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, 87 Xiangya Road, 410008, Changsha, Hunan, China. ORCID
Li Zhang: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA.
Yihui Li: Department of Pharmacy, Changsha Hospital of Traditional Medicine, 22 Xingsha Avenue, 410100, Changsha, Hunan, China.
Wenjuan Zhang: Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jianjun Wang: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA.
Cuiyun Cai: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, 87 Xiangya Road, 410008, Changsha, Hunan, China. ORCID
Xi Lin: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA. xlin2@emory.edu.
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.
References
Mol Ther. 2017 Mar 1;25(3):780-791
[PMID: 28254438]
