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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >In vivo repopulation ability of genetically corrected bone marrow cells from Fanconi anemia patients
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In vivo repopulation ability of genetically corrected bone marrow cells from Fanconi anemia patients

机译：范可尼贫血患者经基因校正的骨髓细胞的体内繁殖能力

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Fanconi anemia (FA) is a rare inherited genomic instability syndrome representing one of the best examples of hematopoietic stem cell deficiency. Although FA might be an excellent candidate for bone marrow (BM) genetic correction ex vivo, knockout animal models are not sufficient to guide preclinical steps, and gene therapy attempts have proven disappointing so far. Contributing to these poor results is a characteristic and dramatic early BM-cells die-off when placed in culture. We show here that human primary FA BM cell survival can be ameliorated by using specific culture conditions that limit oxidative stress. When coupled with retrovi-rus-mediated transfer of the main complementation group FANCA-cDNA, we could achieve long-term reconstitution of the stem cell compartment both in vitro and in vivo. Gene-corrected BM cultures grew for >120 days, and after cultured cell transplantation into NOD/SCID mice, clonogenic human cells carrying the FANCA trans-gene could be detected 6 months after transduction. By comparison, untransduced cells died in culture by 15 days. Of necessity for ethical reasons, experiments were conducted on a very limited number of primary BM cells. By using low cytokine regimen and conditions matching regulatory requirements, a contingent of gene-corrected cells slowly emerges with an unmet potential for in vivo engraftment. Future therapeutic applications of stem cells might be expanding from these data. In addition, we provide a model of gene-corrected human primary cell growth that carries the potential to better delineate the combined role of both DNA damage and oxidative stress in the pathogenesis of FA.
机译：范科尼贫血（FA）是一种罕见的遗传性基因组不稳定性综合征，代表造血干细胞缺乏症的最佳例证之一。尽管FA可能是离体骨髓（BM）基因校正的极佳候选者，但基因剔除动物模型不足以指导临床前步骤，到目前为止，基因治疗的尝试令人失望。造成这些不良结果的一个特征是，当置于培养物中时，早期的BM细胞会大量死亡。我们在这里显示，可以通过使用限制氧化应激的特定培养条件来改善人类原发性FA BM细胞的存活率。当结合逆转录病毒介导的主要互补基团FANCA-cDNA的转移时，我们可以在体外和体内实现干细胞区室的长期重建。经过基因校正的BM培养物生长超过120天，并且在将细胞移植到NOD / SCID小鼠中后，可以在转导后6个月检测到携带FANCA转基因的克隆人细胞。相比之下，未转导的细胞在培养中死亡15天。出于伦理上的考虑，有必要对数量非常有限的原代BM细胞进行实验。通过使用低细胞因子方案和符合法规要求的条件，缓慢出现了基因校正的细胞，在体内植入的潜力尚未得到满足。从这些数据来看，干细胞的未来治疗应用可能正在扩展。此外，我们提供了经过基因校正的人类原代细胞生长模型，该模型具有更好地描述DNA损伤和氧化应激在FA发病机理中的组合作用的潜力。

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