文章：

X连锁SCID基因治疗后白血病的发生

Occurrence of leukaemia following gene therapy of X-linked SCID

原文发布日期：2003-07-01

DOI: 10.1038/nrc1122

类型: Review Article

开放获取: 否

要点：

1. Gene therapy for blood-cell diseases can be performed with retroviral vectors that insert into the genome of haematopoietic stem cells.
2. A recent trial of gene therapy for infants with X-linked severe combined immune deficiency (XSCID) successfully restored the immune systems of most subjects.
3. Two subjects developed T-cell leukaemia more than 2 years after gene therapy commenced. This cancer seems to be caused by retroviral-vector activation of a cellular oncogene at the site of integration, a process known as 'insertional oncogenesis'.
4. The complication of leukaemia has not occurred in any other clinical trial, nor in any large animal model that used retroviral vectors to modify haematopoietic stem cells. Leukaemia has been linked to vector integration in only one mouse study using this approach.
5. Multiple factors could have contributed to the development of leukaemia in the patients involved in this trial. These include the high level of engraftment and expansion of the genetically modified cells, unique properties of the haematopoietic stem and progenitor cells in bone marrow of X-linked SCID patients, the immune deficiency of the X-linked SCID patients and/or the transferred gene itself.
6. Further use of current gene-transfer methods for the treatment of SCID poses an ethical dilemma in the consideration of the complex benefits and risks.
7. It might be possible to develop retroviral vectors or other gene-therapy methods that are less likely to lead to insertional oncogenesis and still retain the therapeutic benefits. The use of tissue-specific, regulated transcription units should, in principle, diminish the risk of proto-oncogene transactivation.

要点翻译：

1. 针对血液疾病的基因治疗可采用逆转录病毒载体进行，这些载体能整合入造血干细胞的基因组。
2. 近期一项针对X连锁重症联合免疫缺陷症（XSCID）婴儿的基因治疗试验成功恢复了多数受试者的免疫系统。
3. 两名受试者在基因治疗启动两年多后罹患T细胞白血病。这种癌症似乎是由逆转录病毒载体在整合位点激活细胞癌基因所致，该过程被称为"插入性肿瘤发生"。
4. 白血病并发症未在其他临床试验或使用逆转录病毒载体修饰造血干细胞的大型动物模型中出现。仅有一项采用此方法的小鼠研究表明白血病与载体整合存在关联。
5. 该试验中患者白血病的发生可能涉及多重因素：包括基因修饰细胞的高植入水平和扩增程度、X连锁SCID患者骨髓中造血干细胞与祖细胞的独特特性、患者本身的免疫缺陷状态和/或所转入基因本身。
6. 在当前权衡复杂获益与风险的前提下，进一步应用现有基因转移技术治疗SCID面临伦理困境。
7. 或可开发新型逆转录病毒载体或其他基因治疗方法，在保留疗效的同时降低插入性肿瘤发生风险。采用组织特异性调控转录单元原则上应能降低原癌基因反式激活的风险。

英文摘要：

Recombinant viral vectors have allowed gene transfer to be developed as a promising approach to the treatment of genetic diseases. Recently, gene therapy of children with X-linked severe combined immune deficiency resulted in impressive levels of immune reconstitution — a triumph that was later overshadowed by the development of leukaemia in two patients. What were the causes of this cancer, and how can the therapeutic benefits of gene therapy be achieved while minimizing risk to the patient?

摘要翻译： 

重组病毒载体使基因转移成为治疗遗传病的一种有前景的方法。最近，对X连锁重症联合免疫缺陷患儿进行的基因治疗实现了令人印象深刻的免疫重建——这一胜利后来被两名患者罹患白血病的阴影所笼罩。这种癌症的起因是什么？又如何在实现基因治疗益处的同时，将患者风险降至最低？

原文链接：

Occurrence of leukaemia following gene therapy of X-linked SCID