Science子刊封面:基因疗法新突破,成功恢复耳聋小鼠听力
2015/07/11
7月8日,在线发表在《科学转化医学》(Science Translational Medicine)杂志上的一项研究中,来自波士顿儿童医院和哈佛医学院的科学家们使用基因疗法成功修复了耳聋小鼠的听力。目前,这些被治疗的小鼠已经保持听觉能力超过2个月。


7月8日,在线发表在《科学转化医学》(Science Translational Medicine)杂志上的一项研究中,来自波士顿儿童医院和哈佛医学院的科学家们使用基因疗法成功修复了耳聋小鼠的听力。

目前,已知的能够导致耳聋的基因有70多种,该研究选择的是TMC1。TMC1是基因性耳聋的常见诱因,占4%-8%;同时TMC1编码的蛋白在听力中起着关键的作用,能够帮助将声音转换成电信号传递到大脑。

研究人员在两种突变类型的小鼠中测试了这种基因疗法;一种是TMC1敲除小鼠,是人类隐性TMC1突变很好的模型。另一种小鼠模型叫Beethoven,有一个特异性的 TMC1突变,是TMC1相关耳聋的显性形式,且不如隐性常见。


为了导入健康的基因,研究小组将其插入到工程病毒AAV1(Adeno-Associated Virus 1)中,一同插入的还有一个启动子。该启动子仅在内耳的毛细胞中启动健康基因。

研究结果发现,在隐性耳聋模型中,使用TMC1基因疗法修复了毛细胞对声音响应的感知能力,产生了可测量的电流,也修复了脑干听力区域的活性。更重要的是,耳聋小鼠恢复了听力。在显性模型中,TMC2基因疗法部分修复了耳聋小鼠的听力。

目前,这些被治疗的小鼠已经保持听力能力超过2个月,研究人员计划进一步优化他们的方法,并且跟踪小鼠看它们的听力能否保持更久。哈佛医学院的副教授Jeffrey Holt表示,未来希望与波士顿儿童医院的耳鼻喉科以及一些其它机构合作,在5-10年内开展TMC1基因治疗的临床试验。

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  • Tmc gene therapy restores auditory function in deaf mice

    Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mouse models of genetic deafness. We focused on DFNB7/11 and DFNA36, which are autosomal recessive and dominant deafnesses, respectively, caused by mutations in transmembrane channel–like 1 (TMC1). Mice that carry targeted deletion of Tmc1 or a dominant Tmc1 point mutation, known as Beethoven, are good models for human DFNB7/11 and DFNA36. We screened several adeno-associated viral (AAV) serotypes and promoters and identified AAV2/1 and the chicken β-actin (Cba) promoter as an efficient combination for driving the expression of exogenous Tmc1 in inner hair cells in vivo. Exogenous Tmc1 or its closely related ortholog, Tmc2, were capable of restoring sensory transduction, auditory brainstem responses, and acoustic startle reflexes in otherwise deaf mice, suggesting that gene augmentation with Tmc1 or Tmc2 is well suited for further development as a strategy for restoration of auditory function in deaf patients who carry TMC1 mutations.

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