摘要
噬血细胞性淋巴组织细胞增生症,指的是一种严重且往往致命的免疫调节异常的病症。它主要由于T细胞和巨噬细胞的不受控制的活化和增殖引起。许多遗传缺陷,主要包括缺陷性颗粒体胞吐与效应细胞的细胞毒作用已经被确定,它们的特性在分子和细胞水平上被充分的检定。这些条件限制了治疗的选择性,此外考虑到造血系统的致病基因的主要限制,它们已经成为对造血细胞进行基因治疗的有吸引力的研究靶标。在穿孔素缺乏的HLH小鼠模型上进行的临床前研究表明,使用慢病毒载体转移自体造血干细胞(HSC )的基因可引起疾病表型的校正。在X连锁淋巴增生性疾病( XLP1 )鼠模型上, HSC基因的转移能校正该疾病的免疫学表现。这些令人鼓舞的小鼠实验,为进一步开发临床应用的方案开辟了道路。另一种方法是校正缺陷的T细胞,因为这方法比HSC基因疗法更安全,并且可以允许通过移植功能基因修饰的效应T细胞对HLH进行早期控制。这两种治疗对策现在都处在开发阶段,HLH的一定遗传形式的基因治疗方案可能很快进入临床试验。
关键词: 基因疗法、造血干细胞移植、噬血细胞性淋巴组织细胞增生症、慢病毒载体。
Current Gene Therapy
Title:Gene Therapy for Haemophagocytic Lymphohistiocytosis
Volume: 14 Issue: 6
Author(s): Claire Booth, Marlene Carmo and H. Bobby Gaspar
Affiliation:
关键词: 基因疗法、造血干细胞移植、噬血细胞性淋巴组织细胞增生症、慢病毒载体。
摘要: Haemophagocytic lymphohistiocytosis (HLH) describes a severe and often fatal immunodysregulatory disorder caused primarily by the uncontrolled activation and proliferation of T cells and macrophages. A number of genetic defects mainly involving defective granule exocytosis and effector cell cytotoxicity have been identified and well characterised at the molecular and cellular level. These conditions have limited therapeutic options and given the predominant restriction of the causative gene to the haematopoietic system, they have become attractive targets for haematopoietic cell gene therapy. Pre clinical studies in murine models of HLH due to perforin deficiency have shown correction of the disease phenotype as a result of autologous haematopoietic stem cell (HSC) gene transfer using lentiviral vectors. In a murine model of X-linked lymphoproliferative disease (XLP1), HSC gene transfer is able to correct the immunological manifestations of the disease. These encouraging murine studies have led to further work to develop clinically applicable strategies. An alternative approach is to correct defective T cells as this approach is safer than HSC gene therapy and may allow early control of the HLH through the engraftment of functional gene modified effector T cells. Both strategies are now in development and a gene therapy option for certain genetic forms of HLH may soon enter clinical trials.
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Cite this article as:
Booth Claire, Carmo Marlene and Gaspar Bobby H., Gene Therapy for Haemophagocytic Lymphohistiocytosis, Current Gene Therapy 2014; 14 (6) . https://dx.doi.org/10.2174/1566523214666140918112113
DOI https://dx.doi.org/10.2174/1566523214666140918112113 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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