Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
University of Washington School of Medicine, Seattle, WA, USA.
Br J Haematol. 2021 Jan;192(1):33-49. doi: 10.1111/bjh.16807. Epub 2020 Jun 7.
Genome editing therapies represent a significant advancement in next-generation, precision medicine for the management of haematological diseases, and CRISPR/Cas9 has to date been the most successful implementation platform. From discovery in bacteria and archaea over three decades ago, through intensive basic research and pre-clinical development phases involving the modification of therapeutically relevant cell types, CRISPR/Cas9 genome editing is now being investigated in ongoing clinic trials. Despite the widespread enthusiasm brought by this new technology, significant challenges remain before genome editing can be routinely recommended and implemented in the clinic. These include risks of genotoxicity resulting from off-target DNA cleavage or chromosomal rearrangement, and suboptimal efficacy of homology-directed repair editing strategies, which thus limit therapeutic options. Practical hurdles such as high costs and inaccessibility to patients outside specialised centres must also be addressed. Future improvements in this rapidly developing field should circumvent current limitations with novel editing platforms and with the simplification of clinical protocols using in vivo delivery of editing reagents.
基因组编辑疗法代表了下一代血液病精准医学的重大进展，而 CRISPR/Cas9 迄今为止是最成功的实施平台。从三十多年前在细菌和古菌中的发现，到涉及对治疗相关细胞类型进行修饰的密集基础研究和临床前开发阶段，CRISPR/Cas9 基因组编辑现在正在正在进行的临床试验中进行研究。尽管这项新技术带来了广泛的热情，但在基因组编辑能够常规推荐和应用于临床之前，仍然存在重大挑战。这些挑战包括脱靶 DNA 切割或染色体重排引起的遗传毒性风险，以及同源定向修复编辑策略的效果不理想，从而限制了治疗选择。此外，高成本和除专业中心外的患者无法获得等实际障碍也必须得到解决。在这个快速发展的领域的未来改进，应该通过使用新型编辑平台和简化使用体内编辑试剂的临床方案来规避当前的局限性。
