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摘要 : 治疗遗传性疾病的一种方法是修复缺陷基因,但是这已经证明在干细胞具有挑战性。现在,意大利圣拉斐尔科学研究所等处的科学家在人类造血干细胞(HSCs)中成功进行的定向基因组编辑。相关文章发表于2014年5月28日的《Nature》杂志上。


Luigi Naldini 及同事在本文中报告了在人类造血干细胞(HSCs)中成功进行的定向基因组编辑。他们通过量身定制输送平台和培养条件克服了以前所存在的障碍。这种方法的治疗潜力通过向来自健康供者和一位“与X-相关的严重复合免疫缺陷症”(SCID-X1)患者的HSCs的IL2RG基因的一个突变热点中插入一个纠正性cDNA得到了演示。



Targeted genome editing in human repopulating haematopoietic stem cells

Pietro Genovese, Giulia Schiroli, Giulia Escobar, Tiziano Di Tomaso, Claudia Firrito,Andrea Calabria, Davide Moi, Roberta Mazzieri, Chiara Bonini, Michael C. Holmes, Philip D. Gregory, Mirjam van der Burg, Bernhard Gentner, Eugenio Montini, Angelo Lombardo &Luigi Naldini

Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RGgene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RGmutations. These results open up new avenues for treating SCID-X1 and other diseases.

对应Nature杂志: 2014年6月12日Nature杂志精选

来源: Nature中文 浏览次数:59


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