人源化模型是块砖，哪里需要哪里搬？来了解各类位点突变致病研究【罕见病十宗罪8】

家族性自主神经失调综合征（Familial dysautonomia syndrome, FD）是一种少见的家族性常染色体隐性遗传病，主要以神经功能障碍、特别是自主神经失调为特征的一组临床症状。该病又称Riley-Day综合征、家族性自主神经功能不全症、中枢性自主神经不全综合征等。

超过9%的FD个体的纯合突变为ELP1基因的20内含子发生IVS20+6T>C突变，这种突变破坏了U1小核核糖核蛋白与内含子20供体剪接位点的碱基配对，导致外显子20编码序列的跳跃。该转录本的错误剪接在转录本中引入了移码，并且该mRNA的翻译产生截短的79kDa蛋白质^[1-2]。

使用小鼠模型研究改变人类细胞剪接过程是充满挑战的，因为两者剪接过程不同^[3]，对于该内含子点突变导致的疾病研究更是如此。已有文献表明，纯合敲除该基因会导致胚胎致死；而直接在野生型小鼠中表达带有人源突变的基因，可能由于表达了正常水平的内源性小鼠ELP1，故没有明显疾病表型^[4-6]。为此，赛业生物自主研发了ELP1全基因组人源化小鼠，及在此基础上构建的热门点突变人源化疾病模型。

不仅是上述提及的疾病，针对视网膜色素变性（RP）、黄斑变性（AMD）、帕金森病（PD）等多种疾病类型，如果要深入研究其致病机理，长片段甚至全基因组人源化小鼠是更好的选择。但全基因组替换所需的技术难度高，大规模引入的外源序列可能会影响原本基因的表达调控。

为此，赛业生物启动了HUGO-GT^TM计划，基于自主研发的TurboKnockout-Pro技术，对鼠源基因实现原位替换，成功构建了涵盖更丰富干预靶点的全基因组人源化小鼠。HUGO-GT^TM小鼠搭载了更高效的大片段载体融合技术，可以作为万能模板进行针对性的突变定制服务，是更贴近真实世界生物机制的药物临床前研究模型。

注：HUGO-GT^TM即Humanized Genomic Ortholog for Gene Therapy

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