在人类造血干细胞中准CRISPR/Cas9β-环球基因
Daniel P Dever1, Rasmus O Bak1, Andreas Reinisch2
1Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
Nature
|November 8, 2016
概括
这项研究引入了CRISPR/Cas9基因编辑系统,用于纠正血造干细胞中的HBB基因,为状细胞疾病等β-血红蛋白病提供了潜在的治疗方法.
科学领域:
- 遗传学和分子生物学
- 血液学
- 基因治疗
背景情况:
- 包括状细胞病和β-血病在内的β-血球蛋白病是影响全球数百万人的遗传性血液疾病.
- 目前的治疗方法有限, 凸显了基因纠正等治疗策略的必要性.
- 血造干细胞移植提供一种潜在的治疗方法,
研究的目的:
- 开发和验证CRISPR/Cas9基因编辑系统,以精确纠正血造干细胞中的HBB基因.
- 建立一个有效的方法来丰富基因编辑的造血干细胞和祖细胞.
- 在基因纠正后证明成人β-环球蛋白表达的功能恢复.
主要方法:
- 使用CRISPR/Cas9系统与Cas9核核蛋白和腺相关病毒载体在HBB基因进行同源重组.
- 开发了一种丰富策略,以隔离具有高向整合率 (> 90%) 的造血干细胞和前代细胞.
- 将患者衍生细胞分化成红细胞以评估功能基因表达.
主要成果:
- 在血液构造干细胞中的HBB位点实现高效同源重组.
- 基因编辑细胞的纯度达到90%以上.
- 在分化红细胞中证明了成人β- 全球蛋白 (HbA) mRNA表达的恢复,证实了正确的转录调节.
结论:
- 介绍了基于CRISPR的强大基因编辑方法,用于血液构造干细胞的HBB位点的同源重组.
- 开发的丰富策略显著提高精确编辑的细胞的产量.
- 这种方法代表了开发下一代beta-hemoglobinopathies治疗的前临床进展.
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