CRISPR剪掉多余的染色体，为治疗唐氏综合症带来新希望

诸平

据PNAS NEXUS2025年2月23日提供的消息,CRISPR剪掉多余的染色体，为治疗唐氏综合症带来新希望(CRISPR Snips Away Extra Chromosomes, Offering New Hope for Down Syndrome Treatment)。

Fig. 1 A proof-of-concept study shows that CRISPR-Cas9 can eliminate extra chromosome copies in Down syndrome cells. The method restores normal gene function but is not yet ready for human trials.

科学家们正在探索基因编辑作为一种在细胞水平上纠正三体病(trisomy)的方法。利用CRISPR-Cas9，研究人员成功地去除了唐氏综合症细胞系(Down syndrome cell lines)中21号染色体的额外拷贝，恢复了正常的基因表达。(Scientists are exploring gene editing as a way to correct trisomy at the cellular level. Using CRISPR-Cas9, researchers successfully removed extra copies of chromosome 21 in Down syndrome cell lines, restoring normal gene expression.)

这一突破表明，随着进一步的发展，类似的方法可以应用于神经元(neurons)和神经胶质细胞(glial cells)，为患有这种疾病的人提供一种潜在的治疗方法。相关研究结果于2025年2月18日已经在《美国国家科学院院刊》{Proceedings of the National Academy of Sciences (PNAS)}的兄弟期刊”PNAS Nexus”网站发表——Ryotaro Hashizume(橋詰 令太郎), Sachiko Wakita, Hirofumi Sawada, Shin-ichiro Takebayashi, Yasuji Kitabatake, Yoshitaka Miyagawa, Yoshifumi S Hirokawa, Hiroshi Imai, Hiroki Kurahashi. Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells. PNAS Nexus , 2025, 4(2): pgaf022. DOI: 10.1093/pnasnexus/pgaf022. Epub 18 February 2025. https://doi.org/10.1093/pnasnexus/pgaf022

参与此项研究的有来自日本三重大学(Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; Laboratory of Molecular and Cellular Biology, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, Japan; Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan)、日本三重大学医院（Department of Genomic Medicine, Mie University Hospital, Tsu, Mie 514-8507, Japan; Pathology Division, Mie University Hospital, Tsu, Mie 514-8507, Japan）、日本大阪大学(Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan)、日本东京的日本医学院(Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan)、日本丰市的藤田健康大学（Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan）的研究人员。

基因编辑治疗三体病(Gene Editing for Trisomy Treatment)

根据日本三重大学医学研究生院(Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan)橋詰 令太郎（Ryotaro Hashizume）博士领导的一项在实验室培养的细胞中进行的概念验证研究，科学家们正在探索基因编辑作为一种在细胞水平上治疗三体病的潜在方法。当一个人有额外的21号染色体拷贝时，唐氏综合症就会发生。唐氏综合症是由三体病引起的，其中21号染色体有三个副本，而不是通常的两个，导致智力发育障碍和其他并发症。大约每700个新生儿中就有一个受到这种情况的影响。虽然这种情况很容易在发展的早期诊断出来，但目前还没有治疗方法。还没有有效的技术来消除细胞中多余的染色体，这是唐氏综合症的根本原因。

日本的研究小组利用CRISPR-Cas9基因组编辑技术，靶向并去除多余的21号染色体，成功率高达37.5%。此外，他们证实，在染色体正常化的细胞中，基因表达模式、细胞增殖速度和抗氧化能力等特征也恢复到正常水平。这一研究成果是朝着实现“染色体治疗”迈出的重要一步。“染色体治疗”旨在去除唐氏综合症的根本原因——多余的染色体。预计将有助于预防和改善与该疾病相关的各种并发症。此外，它有可能为围绕产前诊断的讨论引入一种新的“治疗”选择。

在这项研究中，橋詰 令太郎（Ryotaro Hashizume）及其同事使用CRISPR-Cas9基因编辑系统从21号三体细胞系中去除额外的染色体。这些细胞来源于多能干细胞和皮肤成纤维细胞。该技术能够识别并精确定位复制的染色体，确保在移除后，每个细胞保留来自每个亲本的一个拷贝，而不是两个相同的拷贝。.

Fig. 2 A graphical abstract summarizes the approach. Credit: Editage

通过抑制细胞的自然DNA修复机制，研究人员提高了去除多余染色体的效率。他们的发现表明，这一过程恢复了编辑细胞中正常的基因表达和细胞功能。

未来医疗干预的潜力（Potential for Future Medical Interventions）

虽然很有希望，但这种方法还没有准备好用于生物体，因为它也可以改变剩余的染色体。然而，研究人员相信，类似的方法最终可以应用于神经元（neurons ）和神经胶质细胞（glial cells），为未来治疗唐氏综合症患者铺平道路。

本研究得到了日本科学促进会的资助(Japan Society for the Promotion of Science KAKENHI Grant Numbers JP16K09964, JP16K15242, and JP21K06835)。

上述介绍仅供参考，欲了解更多信息敬请注意浏览原文和相关报道。

Mie University. Innovative Approach Developed for Removing Extra Chromosome 21 in Cells from Individuals with Down Syndrome Using CRISPR-Cas9 Genome Editing Technology. 19 Feb 2025

Abstract

Human trisomy 21, responsible for Down syndrome, is the most prevalent genetic cause of cognitive impairment and remains a key focus for prenatal and preimplantation diagnosis. However, research directed toward eliminating supernumerary chromosomes from trisomic cells is limited. The present study demonstrates that allele-specific multiple chromosome cleavage by clustered regularly interspaced palindromic repeats Cas9 can achieve trisomy rescue by eliminating the target chromosome from human trisomy 21 induced pluripotent stem cells and fibroblasts. Unlike previously reported allele-nonspecific strategies, we have developed a comprehensive allele-specific (AS) Cas9 target sequence extraction method that efficiently removes the target chromosome. The temporary knockdown of DNA damage response genes increases the chromosome loss rate, while chromosomal rescue reversibly restores gene signatures and ameliorates cellular phenotypes. Additionally, this strategy proves effective in differentiated, nondividing cells. We anticipate that an AS approach will lay the groundwork for more sophisticated medical interventions targeting trisomy 21.