Sci Adv:基因编辑视网膜感光细胞治疗遗传性致盲疾病研究获进展

2019-04-18 不详 中国科大

近日,中国科学技术大学生命科学与医学部教授薛天研究组、中国科学院神经科学研究所研究员仇子龙研究组合作,结合视觉神经生物医学与创新基因编辑技术,首次通过同源重组修复方法(Homology directed repair, HDR)在小鼠视网膜非分裂感光细胞中实现精准基因修复,使视网膜色素变性小鼠重获部分视觉功能。

近日,中国科学技术大学生命科学与医学部教授薛天研究组、中国科学院神经科学研究所研究员仇子龙研究组合作,结合视觉神经生物医学与创新基因编辑技术,首次通过同源重组修复方法(Homology directed repair, HDR)在小鼠视网膜非分裂感光细胞中实现精准基因修复,使视网膜色素变性小鼠重获部分视觉功能。

视网膜色素变性是一种常见遗传性眼科疾病,表征为患者视网膜内感光细胞逐渐退化,出生后伴随严重夜盲,视觉区域逐渐减小直至彻底失明,尚无有效治疗手段。CRISPR-Cas9基因编辑是治疗遗传性疾病的潜在手段之一,切割基因组后一般会发生两种DNA修复机制:非同源末端连接(NHEJ)和同源重组修复。HDR可精准将错误基因根据模板修复为正确序列,具有更为优秀的治疗遗传性疾病潜力。直接基因编辑修复受遗传突变影响器官的成体细胞,可在定点恢复受累器官功能的同时又不触及生殖细胞,是安全有效的基因编辑治疗遗传疾病策略。但自然发生的HDR依赖于细胞有丝分裂,对于出生后失去分裂能力的多种体细胞(例如感光细胞)来说,HDR发生效率极低,难以实现在体基因修复。这成为阻碍CRISPR-Cas9基因编辑技术用于成体体细胞治疗遗传性疾病的关键点。

为了解决上述问题,实现HDR对视网膜色素变性等遗传性疾病的精准治疗,该研究在CRISPR/Cas9基础上,创新引入了MS2-RecA复合蛋白系统。RecA为原核表达的可促进同源重组的蛋白酶,研究人员通过改造获得具有MS2结合区的向导RNA,使MS2可与其结合。MS2-RecA复合蛋白即可在DNA切割部位附近招募更多模板DNA,并协助同源重组的发生,从而提高在体同源重组修复的效率。这种利用Cas9/RecA的新型基因编辑方法被称为Targeted-RecA Enhanced homology-Directed repair,简称TRED。利用这一方法,该研究成功实现了TRED矫正非分裂期感光细胞的基因突变,在基因水平、cDNA水平和蛋白水平上,修复了视网膜内视杆细胞的视网膜色素变性突变,遏制部分视杆和视锥细胞的退化,修复视网膜色素变性小鼠的部分视觉感光能力。

该研究实现了出生后非分裂细胞的同源重组基因矫正和相关器官功能修复,提出的TRED方法有望应用于多种人类遗传疾病的在体治疗。

相关成果以In vivo genome editing rescues photoreceptor degeneration via a Cas9/RecA-mediated homology-directed repair pathway为题,在线发表于Science Advances。

原始出处:

Yuan Cai,et al.In vivo genome editing rescues photoreceptor degeneration via a Cas9/RecA-mediated homology-directed repair pathway.Science Advances  17 Apr 2019:Vol. 5, no. 4, eaav3335

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    2019-04-20 zutt
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