Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis—the non-pathogenic hyper-production of red blood cells—that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34⁺ human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the HBA1 gene with an HBB transgene in HSPCs (to restore normal haemoglobin production in cells with a β-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.

一些基因多态性可能导致单基因疾病，而其他多态性可能赋予有益的性状。一个典型的例子是先天性红细胞增多症（红细胞的非致病性过度生成），这是由截短的促红细胞生成素受体引起的。在这里，我们表明，CD34 ⁺人类造血干细胞和祖细胞（HSPC）中Cas9介导的基因组编辑可以重建促红细胞生成素受体的截短形式，从而导致红细胞生成量的大幅增加。我们还表明，将截短的促红细胞生成素受体的 cDNA 表达与先前报道的基因组编辑策略相结合，可在 HSPC 中用HBB转基因完全取代HBA1基因（以恢复具有 β 地中海贫血表型的细胞中的正常血红蛋白产生）赋予编辑后的 ​​HSPC 和健康红细胞表型增殖优势。将人类遗传学知识与精确的基因组编辑相结合，将人类自然变异插入治疗细胞中，可能有助于为遗传性疾病患者提供更安全、更有效的基因组编辑疗法。