CRISPR/Cas gene editing has transformed genetic research and is poised to drive the next generation of gene therapies targeting hematopoietic stem cells (HSCs). However, the installation of the “desired” edit is most often only achieved in a minor subset of alleles. The array of cellular pathways triggered by gene editing tools produces a broad spectrum of “undesired” editing outcomes, including short insertions and deletions (indels) and chromosome rearrangements, leading to considerable genetic heterogeneity in gene-edited HSC populations. This heterogeneity may undermine the effect of the genetic intervention since only a subset of cells will carry the intended modification. Also, undesired mutations represent a potential safety concern as gene editing advances toward broader clinical use. Here, we will review the different sources of “undesired” edits and will discuss strategies for their mitigation and control.

中文翻译：

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了解基因编辑造血干细胞产品的遗传异质性

CRISPR/Cas 基因编辑已经改变了基因研究，并有望推动下一代针对造血干细胞 (HSC) 的基因疗法。然而，“所需”编辑的安装通常只能在等位基因的一小部分子集中实现。基因编辑工具触发的一系列细胞通路会产生广泛的“不需要的”编辑结果，包括短插入和缺失 (indels) 以及染色体重排，导致基因编辑的 HSC 群体中存在相当大的遗传异质性。这种异质性可能会破坏遗传干预的效果，因为只有一部分细胞会携带预期的修饰。此外，随着基因编辑朝着更广泛的临床应用方向发展，不需要的突变也代表了潜在的安全问题。在这里，我们将回顾“不需要的”编辑的不同来源，并讨论缓解和控制它们的策略。