近日，意大利圣拉菲尔科学研究所Luigi Naldini团队开发出基因编辑人类造血干细胞的无化疗移植新方法。该项研究成果于2022年5月25日在线发表在《细胞》杂志上。

　　研究人员表示，造血干细胞/祖细胞基因疗法（HSPC-GT）被证明能成功治疗几种遗传性疾病。HSPC被动员、收获、在体外进行基因纠正，并在进行有毒的清髓性预处理来耗尽骨髓（BM）中的修饰细胞后进行输注。

　　研究人员发现，动员剂为外源细胞的无缝移植创造了机会，这些细胞有效地竞争那些被动员的细胞，从而重新填充枯竭的骨髓。竞争优势来自于体外培养过程中对动员剂对HSPC不利影响的拯救，并且可以通过利用优化的mRNA传递的移植效应因子瞬时过表达而进一步加强。研究人员在高IgM综合征的小鼠模型中显示了疗效，并在人类血型嵌合小鼠中进一步发育，显示了其与基因转移和编辑策略相结合的适用性和多功能性。总的来说，这些发现提供了一个潜在的有价值的策略，为更广泛和更安全地使用HSPC-GT铺平了道路。

　　附：英文原文

　　Title: Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells

　　Author: Attya Omer-Javed, Gabriele Pedrazzani, Luisa Albano, Sherash Ghaus, Claire Latroche, Maura Manzi, Samuele Ferrari, Martina Fiumara, Aurelien Jacob, Valentina Vavassori, Alessandro Nonis, Daniele Canarutto, Luigi Naldini

　　Issue&Volume: 2022-05-25

　　Abstract: Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) is proving successful to treat several genetic diseases. HSPCs are mobilized, harvested, genetically corrected ex vivo, and infused, after the administration of toxic myeloablative conditioning to deplete the bone marrow (BM) for the modified cells. We show that mobilizers create an opportunity for seamless engraftment of exogenous cells, which effectively outcompete those mobilized, to repopulate the depleted BM. The competitive advantage results from the rescue during ex vivo culture of a detrimental impact of mobilization on HSPCs and can be further enhanced by the transient overexpression of engraftment effectors exploiting optimized mRNA-based delivery. We show the therapeutic efficacy in a mouse model of hyper IgM syndrome and further developed it in human hematochimeric mice, showing its applicability and versatility when coupled with gene transfer and editing strategies. Overall, our findings provide a potentially valuable strategy paving the way to broader and safer use of HSPC-GT.

　　DOI: 10.1016/j.cell.2022.04.039

　　Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00537-2