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
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
复制标题
病毒介导的 Kcnq1 基因替代疗法在未成熟的 scala 介质中恢复了人类 Jervell 和 Lange-Nielsen 耳聋综合征小鼠模型的听力
DOI：
10.15252/emmm.201404929
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发表时间：
2015-08-01
影响因子：
11.1
通讯作者：
Lin, Xi
中科院分区：
文献类型：
--
作者：
Chang, Qing;Wang, Jianjun;Lin, Xi
钾离子通道亚基KCNQ 1的突变导致人类严重先天性耳聋Jervell和Lange-Nielsen（JLN）综合征。我们在JLN综合征小鼠模型（Kcnq 1（-/-）小鼠）中应用基因治疗方法，以防止成年期耳聋的发展。出生后（P0-P2）将携带Kcnq 1表达盒的修饰的腺相关病毒构建体注射到内淋巴中，这导致Kcnq 1在大多数耳蜗边缘细胞中表达，其中天然Kcnq 1仅表达。我们还发现，广泛的异位病毒介导的Kcnq 1转基因表达不影响正常的耳蜗功能。耳蜗形态学检查显示，Kcnq 1（-/-）小鼠的Reissner膜塌陷、毛细胞（HC）和螺旋神经节细胞变性得到纠正。电生理检查显示治疗耳耳蜗内电位正常。此外，听觉脑干反应显示出显着的听力保护注射的耳朵，从20分贝的改善，完全纠正耳聋表型。我们的研究结果表明，第一个成功的基因治疗治疗基因缺陷，特别是影响血管纹的功能，这是一个主要的网站受遗传性听力损失的基因突变。
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 20dB 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.