Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness.
Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness.
复制标题
作者：
听力障碍是最常见的感觉障碍，每1000个新生儿中就有1个存在先天性听力障碍，然而耳聋还没有细胞治疗方法。遗传性耳聋通常是由耳蜗毛细胞发育失败或变性介导的。到目前为止，尚不清楚这种先天性失败是否可以通过治疗干预来减轻。在这里，我们表明听力和前庭功能可以在人类遗传性耳聋的小鼠模型中得到恢复。使用反义寡核苷酸（ASO）来纠正突变USH1C转录本的前mrna剪接缺陷。216G>A基因，该基因导致人类Usher综合征（Usher），这是导致耳聋和失明的主要遗传原因。用单次全身剂量的ASO治疗新生小鼠部分纠正USH1C。216G>A剪接，增加蛋白表达，改善耳蜗立体纤毛组织，并挽救小鼠耳蜗毛细胞、前庭功能和听力。我们的研究结果显示了ASOs在治疗耳聋方面的治疗潜力，并提供了证据，证明先天性耳聋可以通过早期治疗来纠正基因表达而有效克服。
Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in ~1 in 1000 newborns, and yet there is no cellular cure for deafness. Hereditary deafness is often mediated by the developmental failure or degeneration of cochlear hair cells. Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention. Here we show that hearing and vestibular function can be rescued in a mouse model of human hereditary deafness. An antisense oligonucleotide (ASO) was used to correct defective pre–mRNA splicing of transcripts from the mutated USH1C.216G>A gene, which causes human Usher syndrome (Usher), the leading genetic cause of combined deafness and blindness. Treatment of neonatal mice with a single systemic dose of ASO partially corrects USH1C.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and hearing in mice. Our results demonstrate the therapeutic potential of ASOs in the treatment of deafness and provide evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression.
登录
查看更多内容
影响因子：
64.8
作者：
Wheeler, Thurman M.;Leger, Andrew J.;Pandey, Sanjay K.;MacLeod, A. Robert;Nakamori, Masayuki;Cheng, Seng H.;Wentworth, Bruce M.;Bennett, C. Frank;Thornton, Charles A.
通讯作者：
Thornton, Charles A.
影响因子：
4
作者：
El-Amraoui, A;Petit, C
通讯作者：
Petit, C
影响因子：
30.8
作者：
Verpy, E;Leibovici, M;Petit, C
通讯作者：
Petit, C
影响因子：
5.3
作者：
Ouyang, XM;Yan, D;Liu, XZ
通讯作者：
Liu, XZ
影响因子：
25
作者：
Petit, Christine;Richardson, Guy P.
通讯作者：
Richardson, Guy P.