近日，西班牙能源环境与技术研究中心Juan A. Bueren研究小组领衔的国际研究团队，实现了基因修饰造血干细胞在凡科尼贫血非条件患者中成功移植。2019年9月，国际知名学术期刊《自然—医学》发表了这一成果。

凡科尼贫血（FA）是一种DNA修复综合征，由迄今发现的22个FA基因中的任何一个突变产生。 FANCA突变占全球FA案例的60％以上。临床上，FA与先天性异常和癌症倾向有关。骨髓衰竭是FA的主要病理特征，70-80％的FA患者在生命第一个十年变得明显。

在这项临床研究中，研究人员证明，对于具有FA亚型A的条件化患者，慢病毒介导的造血基因疗法可重复地赋予非基因校正的造血干细胞（HSCs）的植入和增殖优势。插入位点分析揭示了校正的HSC的多能性，并且显示这些细胞的再增殖优势不是由于治疗性原病毒的遗传毒性整合造成的。通过获得的造血祖细胞和T淋巴细胞对DNA交联剂的抗性，显示血液和骨髓细胞的表型校正。此外，在基因标记水平最高的患者中观察到骨髓衰竭中止。在接受FA治疗的非条件患者中，逐步植入经纠正的造血干细胞，支持基因治疗，应该成为这种危及生命的疾病的一种创新的低毒治疗选择。

附：英文原文

Title: Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia

Author: Paula Ro, Susana Navarro, Wei Wang, Rebeca Snchez-Domnguez, Roser M. Pujol, Jos C. Segovia, Massimo Bogliolo, Eva Merino, Ning Wu, Roco Salgado, Mara L. Lamana, Rosa M. Yaez, Jos A. Casado, Yari Gimnez, Francisco J. Romn-Rodrguez, Lara lvarez, Omaira Alberquilla, Anna Raimbault, Guillermo Guenechea, M. Luz Lozano, Laura Cerrato, Miriam Hernando, Eva Glvez, Raquel Hladun, Irina Giralt, Jordi Barquinero, Anne Galy, Nagore Garca de Andon, Ricardo Lpez, Albert Catal, Jonathan D. Schwartz, Jordi Surralls, Jean Soulier, Manfred Schmidt, Cristina Daz de Heredia, Julin Sevilla, Juan A. Bueren

Issue&Volume:Volume 25 Issue 9

Abstract: Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 7080% of patients with FA during the first decade of life5,6. In this clinical study (ClinicalTrials.gov, NCT03157804; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder. In an early-phase lentiviral gene therapy trial, gene-corrected autologous hematopoietic stem cells show sustained engraftment and phenotypic correction in non-conditioned patients with Fanconi anemia.

DOI: 10.1038/s41591-019-0550-z

Source:https://www.nature.com/articles/s41591-019-0550-z