新的基因编辑领域突破口——表观遗传调控（二）
2. 神经系统疾病
▼ 致病机理：神经细胞中由于遗传缺陷导致的疾病
▼ 代表工作：同时另一项突破性的工作则使用一种SunTag（dCas9-10xGCN4）系统融合多个拷贝的转录激活蛋白（p65-HSF1），构建了一种Cre依赖性的SunTag-p65-HSF1（SPH）转基因小鼠模型。使用AAV8将Cre和sgRNAs递送到SPH转基因小鼠中，通过激活内源性神经源性转录因子的表达，在小鼠体内成功地实现了星形胶质细胞直接转化为功能性的神经元[17]。这一研究表明，在不需要使用外源重编程因子或转录因子的前提下，通过转录调控的CRISPR系统可以实现特定细胞的重编程或不同细胞类型之间的转分化，为体外细胞基因治疗遗传疾病提供了新的策略。
图5. Cre诱导的dCas9小鼠[21]
3. 单倍体剂量不足引起的疾病
▼ 致病机理：单倍剂量不足(haploinsufficiency )指一个等位基因突变后，另一个等位基因能正常表达，但这只有正常水平50%的蛋白质不足以维持细胞正常的生理功能。
▼ 代表工作：近日，Science在线发表了一篇使用CRISPRa系统在小鼠中成功修复一种因单倍剂量不足引起的肥胖。研究人员通过AAV在SIM1基因或MC4R基因部分功能丧失的小鼠脑部递送dCas9-vp64和sgRNA的方式成功激活了SIM1或MC4R蛋白的表达，成功抑制了肥胖的表型[18]。这一策略给罹患单倍体剂量不足引起的疾病患者带来转机。
图6. 通过CRISPRa治疗单倍体剂量不足相关疾病[18]
4. 异常甲基化引起的疾病
▼ 致病机理：基因中CpG岛中的5' C经常突变引起高甲基化、羟甲基化等修饰，研究表明这些异常修饰会影响基因的表达调控，最终引起疾病[19]。
▼ 代表工作：脆性X综合征（Fragile X syndrome, FXS）就是一种由FMR1基因5' UTR 区中CGG三核甘酸重复序列扩增突变并高甲基化，使FMR基因沉默而导致的疾病。最近的一项研究通过利用dCas9融合Tet甲基胞嘧啶双加氧酶1（Tet methylcytosine dioxygenase 1, Tet1）转染FXS iPSCs 细胞系，成功靶向诱导FMR基因5' UTR CpG岛去甲基化，为这些因异常甲基化引起的疾病的治疗奠定了基础[20]。
图7. 脆性X综合征相关疾病的表观遗传治疗[20]
怎么样，这次的公众号是不是让大家大开眼界呢？相信通过这四期的公众号，大家已经对基因编辑在疾病治疗中的研究应用有了较为系统的了解，不过“路漫漫其修远兮”，从实验室走到临床还有较为漫长的距离要走。但是大量的实验已经给我们看到了未来疾病治疗的新曙光，相信终有一天，基因编辑治疗的大时代终会到来。
参考文献：（向下滑动查看）
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