Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils
Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils
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DOI：
10.1182/blood-2009-05-222760
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发表时间：
2010-01-28
期刊：
影响因子：
20.3
通讯作者：
Malech, Harry L.
中科院分区：
文献类型：
--
作者：
Kang, Elizabeth M.;Choi, Uimook;Malech, Harry L.
慢性肉芽肿性疾病（CGD）与感染的显著发病率和死亡率相关。第一个CGD基因治疗试验仅导致0.01%至0.1%的中性粒细胞的短期标记。最近的一项研究，使用白消安预处理和SFFV逆转录病毒载体，在2例X连锁CGD患者中实现了超过20%的标记。然而，每标记中性粒细胞的氧化酶校正低于正常值，并且不持续。尽管如此，患者明显受益于严重感染的解决。因此，我们启动了X-CGD的基因治疗试验，以治疗对常规治疗无反应的严重感染。我们用白消安预处理和编码gp 91（phox）的MFGS逆转录病毒载体治疗了3例成人患者，分别实现了26%、5%和4%的中性粒细胞的早期标记，其中2例患者的中性粒细胞的持续长期标记分别为1.1%和0.03%。基因标记的中性粒细胞分别在34个月和11个月内维持了氧化酶活性的完全纠正，这2例患者的感染完全或部分消退。基因标记是多克隆的，没有克隆优势。我们的结论是白消安空调连同MFGS载体能够实现长期的中性粒细胞氧化酶功能的校正足以提供在严重感染的管理中的好处。本研究在www.clinicaltrials.gov注册为#NCT 00394316。（血。2010;115：783-791）
Chronic granulomatous disease (CGD) is associated with significant morbidity and mortality from infection. The first CGD gene therapy trial resulted in only short-term marking of 0.01% to 0.1% of neutrophils. A recent study, using busulfan conditioning and an SFFV retrovirus vector, achieved more than 20% marking in 2 patients with X-linked CGD. However, oxidase correction per marked neutrophil was less than normal and not sustained. Despite this, patients clearly benefited in that severe infections resolved. As such, we initiated a gene therapy trial for X-CGD to treat severe infections unresponsive to conventional therapy. We treated 3 adult patients using busulfan conditioning and an MFGS retroviral vector encoding gp91(phox), achieving early marking of 26%, 5%, and 4% of neutrophils, respectively, with sustained long-term marking of 1.1% and 0.03% of neutrophils in 2 of the patients. Gene-marked neutrophils have sustained full correction of oxidase activity for 34 and 11 months, respectively, with full or partial resolution of infection in those 2 patients. Gene marking is polyclonal with no clonal dominance. We conclude that busulfan conditioning together with an MFGS vector is capable of achieving long-term correction of neutrophil oxidase function sufficient to provide benefit in management of severe infection. This study was registered at www.clinicaltrials.gov as #NCT00394316. (Blood. 2010;115:783-791)