Long-Term Follow-up of Foamy Viral Vector-Mediated Gene Therapy for Canine Leukocyte Adhesion Deficiency
Long-Term Follow-up of Foamy Viral Vector-Mediated Gene Therapy for Canine Leukocyte Adhesion Deficiency
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DOI：
10.1038/mt.2013.34
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发表时间：
2013-05-01
影响因子：
12.4
通讯作者：
Hickstein, Dennis D.
中科院分区：
文献类型：
--
作者：
Bauer, Thomas R., Jr.;Tuschong, Laura M.;Hickstein, Dennis D.
针对X连锁严重联合免疫缺陷病和慢性肉芽肿病（CGD）的γ逆转录病毒载体介导的基因治疗后白血病的发展强调了对接受造血干细胞基因治疗的动物进行长期随访的必要性。在这项研究中，我们报告了四只患有犬白细胞粘附缺陷（CLAD）的狗接受泡沫病毒（FV）载体介导的基因疗法治疗的长期随访（4-7年）。所有四只 CLAD 狗之前都接受了 200 cGy 全身照射的非清髓性调理，然后输注自体 CD34(+) 造血干细胞，这些干细胞由表达犬 CD18 的 FV 载体转导，该 FV 载体从内部鼠干细胞病毒 (MSCV) 启动子表达犬 CD18。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。四只狗中的任何一只都没有出现淋巴样或髓样白血病的临床发展，并且整合位点分析没有揭示插入性肿瘤发生。这些结果显示 CLAD 疾病得到纠正/改善，且没有显着不良事件，这为在人类基因治疗临床试验中使用 FV 载体治疗 1 型白细胞粘附缺陷 (LAD-1) 儿童提供了支持。
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.