Department of Biomedical Engineering and.
Jonas Children's Vision Care and Bernard and Shirlee Brown Glaucoma Laboratory, Columbia University, New York, New York, USA.
J Clin Invest. 2022 May 2;132(9). doi: 10.1172/JCI158287.
Autosomal dominant disorders present unique challenges, as therapeutics must often distinguish between healthy and diseased alleles while maintaining high efficiency, specificity, and safety. For this task, CRISPR/Cas remains particularly promising. Various CRISPR/Cas systems, like homology-directed repair, base editors, and prime editors, have been demonstrated to selectively edit mutant alleles either by incorporating these mutations into sgRNA sequences (near the protospacer-adjacent motif ["near the PAM"]) or by targeting a novel PAM generated by the mutation ("in the PAM"). However, these probability-based designs are not always assured, necessitating generalized, mutation-agnostic strategies like ablate-and-replace and single-nucleotide polymorphism editing. Here, we detail recent advancements in CRISPR therapeutics to treat a wide range of autosomal dominant disorders and discuss how they are altering the landscape for future therapies.
常染色体显性遗传病带来了独特的挑战,因为治疗方法必须在保持高效、特异性和安全性的同时,区分健康和病变等位基因。在这方面,CRISPR/Cas 仍然非常有前景。各种 CRISPR/Cas 系统,如同源定向修复、碱基编辑器和先导编辑,已经被证明可以通过将这些突变整合到 sgRNA 序列中(靠近原间隔基序[靠近 PAM])或通过靶向由突变产生的新 PAM(在 PAM 中),来选择性地编辑突变等位基因。然而,这些基于概率的设计并不总是确定的,因此需要像消融和替换以及单核苷酸多态性编辑这样的通用、无突变策略。在这里,我们详细介绍了 CRISPR 治疗在治疗广泛的常染色体显性遗传病方面的最新进展,并讨论了它们如何改变未来治疗的前景。