基因治疗重大突破：利用基因编辑治疗小鼠耳聋

图示一耳聋男孩

“贝多芬小鼠”由于携带突变Tmc1基因而耳聋，突变Tmc1基因与野生型基因仅一个碱基的差别。2017年12月21日，美国科学家David Liu在Nature发文，利用脂质体将Cas9蛋白和sgRNA转运到突变小鼠内耳细胞，特异性敲除突变的Tmc1基因，而保留野生型Tmc1，从而治疗耳聋。

该方法解决了基因治疗中的几个重要问题：1、利用脂质体作为载体，规避了病毒载体的可能副作用。2、转运进入细胞的蛋白和RNA停留时间有限，避免转运基因导致的副作用。3、利用显微注射到病灶，避免对其他细胞、组织的影响。

Nature评论链接

研究论文摘要：Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited^1,2,3,4,5. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9–guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1^Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9–guide RNA–lipid complexes targeting the Tmc1^Bth allele into the cochlea of neonatal Tmc1^Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1^Bth/+ mice. These findings suggest that protein–RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Nature文章链接

10.1038@nature25164