泡沫病毒载体介导的犬白细胞黏附缺陷症基因治疗的长期随访。

Long-term follow-up of foamy viral vector-mediated gene therapy for canine leukocyte adhesion deficiency.

机构信息

Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

出版信息

Mol Ther. 2013 May;21(5):964-72. doi: 10.1038/mt.2013.34. Epub 2013 Mar 26.

Abstract

The development of leukemia following gammaretroviral vector-mediated gene therapy for X-linked severe combined immunodeficiency disease and chronic granulomatous disease (CGD) has emphasized the need for long-term follow-up in animals treated with hematopoietic stem cell gene therapy. In this study, we report the long-term follow-up (4-7 years) of four dogs with canine leukocyte adhesion deficiency (CLAD) treated with foamy viral (FV) vector-mediated gene therapy. All four CLAD dogs previously received nonmyeloablative conditioning with 200 cGy total body irradiation followed by infusion of autologous, CD34(+) hematopoietic stem cells transduced by a FV vector expressing canine CD18 from an internal Murine Stem Cell Virus (MSCV) promoter. CD18(+) leukocyte levels were >2% following infusion of vector-transduced cells leading to ongoing reversal of the CLAD phenotype for >4 years. There was no clinical development of lymphoid or myeloid leukemia in any of the four dogs and integration site analysis did not reveal insertional oncogenesis. These results showing disease correction/amelioration of disease in CLAD without significant adverse events provide support for the use of a FV vector to treat children with leukocyte adhesion deficiency type 1 (LAD-1) in a human gene therapy clinical trial.

摘要

在采用伽马逆转录病毒载体介导的基因疗法治疗 X 连锁严重联合免疫缺陷病和慢性肉芽肿病(CGD)后出现白血病的情况,强调了对接受造血干细胞基因疗法治疗的动物进行长期随访的必要性。在这项研究中,我们报告了 4 只患有犬白细胞黏附缺陷症(CLAD)的狗接受泡沫病毒(FV)载体介导的基因治疗后的长期随访(4-7 年)。所有 4 只 CLAD 狗以前都接受了非清髓性预处理,总剂量为 200cGy 的全身照射,然后输注自体、CD34+造血干细胞,这些细胞由表达来自内部鼠干细胞病毒(MSCV)启动子的犬 CD18 的 FV 载体转导。输注载体转导细胞后,CD18+白细胞水平>2%,导致 CLAD 表型持续逆转>4 年。四只狗中均未出现淋巴样或髓样白血病的临床发展,整合位点分析也未显示插入性致癌作用。这些结果表明,FV 载体可纠正 CLAD 中的疾病/改善疾病,且无明显不良事件,为在人类基因治疗临床试验中使用 FV 载体治疗白细胞黏附缺陷症 1 型(LAD-1)患儿提供了支持。

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