title: Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome.
abstract: Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1(-/-) mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0-P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner's membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1(-/-) mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss.
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Yeunjung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Binfei
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China hwli@shmu.edu.cn xlin2@emory.edu.
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China hwli@shmu.edu.cn xlin2@emory.edu.
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D003053:Cochlear Duct / Q000502:physiology*; D003638:Deafness / Q000151:congenital / Q000235:genetics* / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D029593:Jervell-Lange Nielsen Syndrome / Q000235:genetics* / Q000628:therapy*; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D014161:Transduction, Genetic; D019076:Transgenes; D016896:Treatment Outcome
chemical_list: D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse
keywords: Jervell and Lange‐Nielsen syndrome; Kcnq1 null mice; gene therapy; hearing restoration; virus