Nienhuis Arthur W, Dunbar Cynthia E, Sorrentino Brian P
Division of Experimental Hematology, Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.
Mol Ther. 2006 Jun;13(6):1031-49. doi: 10.1016/j.ymthe.2006.03.001. Epub 2006 Apr 19.
The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X-linked severe combined immunodeficiency (X-SCID) by gene therapy, indicates that the potential genotoxicity of retroviral integration in hematopoietic cells will remain a consideration in evaluating the relative risks versus benefits of gene therapy for specific blood disorders. Although many unique variables may have contributed to an increased risk in X-SCID patients, clonal dominance or frank neoplasia in animal models, clonal dominance in humans with chronic granulomatous disease, and the ability of retroviral integration to immortalize normal bone marrow cells or convert factor-dependent cells to factor independence suggest that transduction of cells with an integrating retrovirus has the potential for altering their subsequent biologic behavior. The selective pressure imposed during in vitro culture or after engraftment may uncover a growth or survival advantage for cells in which an integration event has affected gene expression. Such cells then carry the risk that subsequent mutations may lead to neoplastic evolution of individual clones. Balancing that risk is that the vast majority of integration events seem to be neutral and that optimizing vector design may diminish the probability of altering gene expression by an integrated vector genome. Several cell culture systems and animal models designed to empirically evaluate the safety of vector systems are being developed and should provide useful data for weighing the relative risks and benefits for specific diseases and patient populations. Gene therapy interventions continue to have enormous potential for the treatment of disorders of the hematopoietic system. The future of such efforts seems bright as we continue to evolve and improve various strategies to make such interventions both effective and as safe as possible.
自首例通过基因疗法治愈的X连锁重症联合免疫缺陷病（X-SCID）患儿报告白血病病例以来，过去3年的经验表明，逆转录病毒整合至造血细胞中潜在的基因毒性，在评估针对特定血液疾病的基因疗法的相对风险与益处时仍需加以考虑。尽管许多独特变量可能导致X-SCID患者风险增加，但动物模型中的克隆优势或明显的肿瘤形成、慢性肉芽肿病患者中的克隆优势，以及逆转录病毒整合使正常骨髓细胞永生化或将因子依赖细胞转变为因子非依赖细胞的能力，均表明用整合型逆转录病毒转导细胞有改变其后续生物学行为的可能性。体外培养期间或植入后施加的选择压力，可能会揭示整合事件影响基因表达的细胞的生长或生存优势。此类细胞随后存在后续突变可能导致单个克隆发生肿瘤性演变的风险。与之平衡的是，绝大多数整合事件似乎是中性的，优化载体设计可能会降低整合的载体基因组改变基因表达的可能性。正在开发几种旨在凭经验评估载体系统安全性的细胞培养系统和动物模型，它们应能为权衡特定疾病和患者群体的相对风险与益处提供有用数据。基因治疗干预对于治疗造血系统疾病仍具有巨大潜力。随着我们不断改进各种策略以使此类干预既有效又尽可能安全，这些努力的前景似乎一片光明。
