Lee Jeong Hyeon, Han Jeong Pil
Graduate School of International Agricultural Technology, Institute of Green BioScience and Technology, Seoul National University, 1447 Pyeongchang-ro, Daewha, Pyeongchang, 25354, Gangwon, Korea.
Mol Diagn Ther. 2024 May;28(3):239-248. doi: 10.1007/s40291-024-00705-1. Epub 2024 Mar 28.
Hemophilia is a genetic disorder that is caused by mutations in coagulation factor VIII (hemophilia A) or IX (hemophilia B) genes resulting in blood clotting disorders. Despite advances in therapies, such as recombinant proteins and products with extended half-lives, the treatment of hemophilia still faces two major limitations: the short duration of therapeutic effect and production of neutralizing antibodies against clotting factors (inhibitor). To overcome these limitations, new hemophilia treatment strategies have been established such as gene therapy, bispecific antibody, and rebalancing therapy. Although these strategies have shown promising results, it is difficult to achieve a permanent therapeutic effect. Advances in the clustered regularly interspaced short palindromic repeat (CRISPR) technology have allowed sustainable treatment by correcting mutated genes. Since genome editing generates irreversible changes in host genome, safety must be ensured by delivering target organs. Therefore, the delivery tool of the CRISPR system is crucial for safe, accurate, and efficient genome editing. Recently, non-viral vector lipid nanoparticles (LNPs) have emerged as safer tools for delivering CRISPR systems than other viral vectors. Several previous hemophilia pre-clinical studies using LNP-CRISPR showed that sufficient and sustainable therapeutic effects, which means that LNP-CRISPR-mediated genome-editing therapy can be a valid option for the treatment of hemophilia. In this paper, we summarize the latest advancements in the successful treatment of hemophilia and the potential of CRISPR-mediated genome-editing therapy using LNPs.
血友病是一种遗传性疾病，由凝血因子VIII（A型血友病）或IX（B型血友病）基因的突变引起，导致血液凝固障碍。尽管在治疗方法上取得了进展，如重组蛋白和半衰期延长的产品，但血友病的治疗仍面临两个主要限制：治疗效果持续时间短以及产生针对凝血因子的中和抗体（抑制剂）。为了克服这些限制，已经建立了新的血友病治疗策略，如基因治疗、双特异性抗体和再平衡疗法。尽管这些策略已显示出有希望的结果，但难以实现永久的治疗效果。成簇规律间隔短回文重复序列（CRISPR）技术的进步使得通过纠正突变基因实现可持续治疗成为可能。由于基因组编辑会在宿主基因组中产生不可逆的变化，因此必须通过将其递送至靶器官来确保安全性。因此，CRISPR系统的递送工具对于安全、准确和高效的基因组编辑至关重要。最近，非病毒载体脂质纳米颗粒（LNPs）已成为比其他病毒载体更安全的CRISPR系统递送工具。先前几项使用LNP-CRISPR的血友病临床前研究表明，其具有充分且可持续的治疗效果，这意味着LNP-CRISPR介导的基因组编辑疗法可能是治疗血友病的有效选择。在本文中，我们总结了血友病成功治疗的最新进展以及使用LNPs的CRISPR介导的基因组编辑疗法的潜力。
