新研究探究了人類造血干細胞的堿基編輯治療
美國哈佛醫(yī)學(xué)院Daniel E. Bauer團隊的一項研究探究了人類造血干細胞（HSC）的堿基編輯治療。相關(guān)論文于2020年3月16日在線發(fā)表在《自然-醫(yī)學(xué)》上。
在這項研究中，研究人員純化了A3A（N57Q）-BE3堿基編輯器，這是人類外周血動員時CD34 +造血干細胞和祖細胞（HSPC）核糖核蛋白（RNP）的電穿孔素。
研究人員觀察到BCL11A紅系增強子在+58處頻繁發(fā)生靶點胞嘧啶堿基編輯。紅細胞子代中的胎兒血紅蛋白（HbF）在堿基編輯或核酸酶編輯后相似。針對BCL11A增強子一個位點的堿基編輯治療，分別預(yù)防了鐮狀細胞病中類紅細胞子代鐮狀化和β地中海貧血患者來源HSPC誘導(dǎo)的血紅蛋白鏈失衡。
此外，BCL11A紅系增強子破壞與HBB -28A> G啟動子突變糾正相結(jié)合可以實現(xiàn)多重有效編輯。后，正如在主要和次要受體動物中的測定結(jié)果，在多譜系衍生的自我更新人類HSCs中可以產(chǎn)生高頻率的堿基編輯，從而在體內(nèi)有效誘導(dǎo)HbF。
總的來說，這些結(jié)果揭示了人類HSPC的RNP堿基編輯可以作為靶向HSC治療基因組修飾替代方法的潛能。
研究人員表示，將核苷酸脫氨酶與可編程DNA結(jié)合蛋白結(jié)合起來進行堿基編輯的方法，是長久治愈血液疾病的潛在治療方式，但這一方法是否適用于造血干細胞仍有待探究。
附：英文原文
Title: Therapeutic base editing of human hematopoietic stem cells
Author: Jing Zeng, Yuxuan Wu, Chunyan Ren, Jasmine Bonanno, Anne H. Shen, Devlin Shea, Jason M. Gehrke, Kendell Clement, Kevin Luk, Qiuming Yao, Rachel Kim, Scot A. Wolfe, John P. Manis, Luca Pinello, J. Keith Joung, Daniel E. Bauer
Issue&Volume: 2020-03-16
Abstract: Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. In this study, we purified A3A (N57Q)-BE3 base editor for ribonucleoprotein (RNP) electroporation of human-peripheral-blood-mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A erythroid enhancer at +58 with few indels. Fetal hemoglobin (HbF) induction in erythroid progeny after base editing or nuclease editing was similar. A single therapeutic base edit of the BCL11A enhancer prevented sickling and ameliorated globin chain imbalance in erythroid progeny from sickle cell disease and β-thalassemia patient-derived HSPCs, respectively. Moreover, efficient multiplex editing could be achieved with combined disruption of the BCL11A erythroid enhancer and correction of the HBB 28A>G promoter mutation. Finally, base edits could be produced in multilineage-repopulating self-renewing human HSCs with high frequency as assayed in primary and secondary recipient animals resulting in potent HbF induction in vivo. Together, these results demonstrate the potential of RNP base editing of human HSPCs as a feasible alternative to nuclease editing for HSC-targeted therapeutic genome modification.
DOI: 10.1038/s41591-020-0790-y
Source: https://www.nature.com/articles/s41591-020-0790-y
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