Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center, Utrecht, The Netherlands.
CDL Research, University Medical Center Utrecht, Utrecht, The Netherlands.
Adv Exp Med Biol. 2023;1396:315-339. doi: 10.1007/978-981-19-5642-3_20.
Genome editing technologies, particularly CRISPR-Cas (clustered regularly interspaced short palindromic repeats (CRISPR) associated nucleases), are redefining the boundaries of therapeutic gene therapy. CRISPR-Cas is a robust, straightforward, and programmable genome editing tool capable of mediating site-specific DNA modifications. The rapid advancements from discovery to clinical adaptation have expanded the therapeutic landscape to treat genetically defined diseases. Together with the technical developments in human DNA and RNA sequencing, CRISPR-directed gene therapy enables a new era to realize precision medicine where pathogenic mutations underlying monogenic disorders can potentially be corrected. Also, protective or therapeutic genomic alterations can be introduced as preventative or curative therapy. Despite its high therapeutic potential, CRISPR-Cas´ clinical translation is still in its infancy and is highly dependent on its efficiency, specificity in gene corrections, and cell-specific delivery. Therefore, this chapter focuses on the challenges and opportunities the CRISPR-Cas toolbox offers together with delivery vehicles to realize its use for therapeutic gene editing. Furthermore, we discuss the obstacles the CRISPR-Cas system faces for successful clinical translation and summarize its current clinical progress.
基因组编辑技术，特别是 CRISPR-Cas（规律成簇间隔短回文重复序列（CRISPR）相关核酸酶），正在重新定义治疗性基因治疗的界限。CRISPR-Cas 是一种强大、简单、可编程的基因组编辑工具，能够介导特定部位的 DNA 修饰。从发现到临床应用的快速进展，扩大了治疗领域，以治疗遗传性疾病。与人类 DNA 和 RNA 测序的技术发展相结合，CRISPR 指导的基因治疗开启了精准医学的新时代，使治疗单基因疾病的潜在致病突变成为可能。此外，还可以引入保护性或治疗性基因组改变作为预防或治疗性治疗。尽管具有很高的治疗潜力，但 CRISPR-Cas 的临床转化仍处于起步阶段，高度依赖于其效率、基因校正的特异性和细胞特异性传递。因此，本章重点介绍 CRISPR-Cas 工具包与传递载体一起提供的挑战和机遇，以实现其在治疗性基因编辑中的应用。此外，我们还讨论了 CRISPR-Cas 系统在成功临床转化方面面临的障碍，并总结了其目前的临床进展。
