Targeted genome editing in human repopulating haematopoietic stem cells.
Targeted genome editing in human repopulating haematopoietic stem cells.
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DOI：
10.1038/nature13420
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发表时间：
2014-06-12
期刊：
影响因子：
64.8
通讯作者：
Naldini, Luigi
中科院分区：
文献类型：
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作者：
Genovese, Pietro;Schiroli, Giulia;Escobar, Giulia;Di Tomaso, Tiziano;Firrito, Claudia;Calabria, Andrea;Moi, Davide;Mazzieri, Roberta;Bonini, Chiara;Holmes, Michael C.;Gregory, Philip D.;van der Burg, Mirjam;Gentner, Bernhard;Montini, Eugenio;Lombardo, Angelo;Naldini, Luigi
通过人工核酸酶进行的靶向基因组编辑使基因治疗能够实现位点特异性转基因整合和基因校正的目标。然而，其在长期可重建造血干细胞（HSCs）中的应用一直难以实现。在此我们表明，对基因转移的低允许性以及同源定向DNA修复途径的有限效率限制了人类造血干细胞中的基因靶向。通过调整递送平台和培养条件，我们克服了这些障碍，并通过移植小鼠的长期多谱系重建造血提供了人类造血干细胞中靶向整合的有力证据。我们通过将校正性cDNA靶向导入健康供体以及一名X连锁重症联合免疫缺陷（SCID - X1）患者的造血干细胞的IL2RG基因，证明了我们策略的治疗潜力。经过基因编辑的造血干细胞维持了正常的造血功能，并产生了功能性淋巴细胞，这些淋巴细胞相较于携带IL2RG破坏性突变的细胞具有选择性生长优势。这些结果为治疗SCID - X1和其他疾病开辟了新途径。
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 Hematopoietic 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 cDNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked Severe Combined Immunodeficiency (SCID-X1). Gene edited HSCs sustained normal hematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open new avenues for treating SCID-X1 and other diseases.
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影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
46.9
作者：
Hockemeyer, Dirk;Soldner, Frank;Beard, Caroline;Gao, Qing;Mitalipova, Maisam;DeKelver, Russell C.;Katibah, George E.;Amora, Ranier;Boydston, Elizabeth A.;Zeitler, Bryan;Meng, Xiangdong;Miller, Jeffrey C.;Zhang, Lei;Rebar, Edward J.;Gregory, Philip D.;Urnov, Fyodor D.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
--
作者：
Akatsuka, Y;Martin, EG;Hansen, JA
通讯作者：
Hansen, JA