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首页> 外文期刊>Journal of the Association for Research in Otolaryngology: JARO >Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment
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Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

机译：用反义寡核苷酸拯救在母细胞小鼠中的外毛细胞依赖于治疗年龄

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摘要

The absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation, Ush1c c.216G A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells. Here, we show that Ush1c c.216AA mice lack OHC function as evidenced by the absence of distortion product otoacoustic emissions (DPOAEs) in response to low-, mid-, and high-frequency tone pairs. This OHC deficit is rescued by treatment with an ASO that corrects expression of Ush1c c.216G A. Interestingly, although rescue of inner hairs cells, as measured by ABR, is achieved by ASO treatment as late as 7 days after birth, rescue of outer hair cells, measured by DPOAE, requires treatment before post-natal day 5. These results suggest that ASO-mediated rescue of both IHC and OHC function is age dependent and that the treatment window is different for the different cell types. The timing of treatment for congenital hearing disorders is of critical importance for the development of drugs such ASO-29 for hearing rescue.
机译：没有功能性外毛细胞是几种形式的遗传性听力障碍的组成部分，包括迎膜综合征，并发听力和视力丧失的最常见原因。对小鼠的反义寡核苷酸（ASO）与人置突变，USH1C C.216G＆GT; A，校正基因表达并显着改善听力，通过听觉诱发的脑干响应（ABR），以及内部和外毛细胞（IHC和OHC）束形态。然而，目前尚不清楚ASO治疗所实现的听力的改善涉及外毛细胞的功能救援。在这里，我们表明USH1C C.216AA小鼠缺乏OHC功能，如响应于低，中和高频音对的缺乏失真产品耳声发射（DPOAE）所证明。这种OCC缺陷通过用ASO治疗来拯救，纠正USH1C C.216G＆GT的表达; A.有趣的是，虽然由ABR测量的内毛细胞拯救在出生后7天后，但是通过DPOAE测量的外毛细胞拯救在产后第5天之前进行治疗。这些结果表明，IHC和OHC函数的aso介导的救援是依赖的年龄，并且治疗窗口对于不同的细胞类型不同。先天性听力障碍治疗的时间对诸如听力救援的诸如-29这样的药物的发展至关重要。

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