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Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease
Frontiers in Immunology ( IF 7.3 ) Pub Date : 2020-11-02 , DOI: 10.3389/fimmu.2020.608653
Elena Blanco 1 , Natalia Izotova 1 , Claire Booth 1, 2 , Adrian James Thrasher 1, 2
Affiliation  

X-linked severe immunodeficiency disease (SCID-X1) is an inherited, rare, and life-threating disease. The genetic origin is a defect in the interleukin 2 receptor γ chain (IL2RG) gene and patients are classically characterized by absence of T and NK cells, as well as presence of partially-functional B cells. Without any treatment the disease is usually lethal during the first year of life. The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (>90%) if an HLA-matched sibling donor is available. However, when alternative donors are used, the success and survival rates are often lower. Gene therapy has been developed as an alternative treatment initially using γ-retroviral vectors to correct the defective γ chain in the absence of pre-conditioning treatment. The results were highly promising in SCID-X1 infants, showing long-term T-cell recovery and clinical benefit, although NK and B cell recovery was less robust. However, some infants developed T-cell acute lymphoblastic leukemia after the gene therapy, due to vector-mediated insertional mutagenesis. Consequently, considerable efforts have been made to develop safer vectors. The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults. This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.



中文翻译:

X连锁严重合并免疫缺陷病患者基因治疗后的免疫重建

X连锁严重免疫缺陷疾病(SCID-X1)是一种遗传,罕见且威胁生命的疾病。遗传起源是白介素2受体γ链的缺陷(白介素2RG基因和患者的经典特征是不存在T细胞和NK细胞以及存在部分功能性B细胞。未经任何治疗,该疾病通常在生命的第一年就致命。这些患者选择的治疗方法是造血干细胞移植,如果可获得HLA匹配的同胞供体,则存活率极高(> 90%)。但是,当使用替代捐赠者时,成功率和存活率通常较低。已经开发出基因疗法作为替代疗法,最初是在没有预处理疗法的情况下使用γ-逆转录病毒载体纠正有缺陷的γ链。尽管NK和B细胞的恢复能力较弱,但该结果在SCID-X1婴儿中具有很高的前景,显示出长期的T细胞恢复和临床益处。然而,基因治疗后,由于载体介导的插入诱变,一些婴儿出现了T细胞急性淋巴细胞白血病。因此,为开发更安全的载体付出了巨大的努力。使用慢病毒载体和低剂量的预处理方案进行的最新临床试验表明,无论儿童还是成人,都具有出色的持续T细胞恢复能力,以及B和NK细胞。这篇综述概述了过去20年中用于治疗SCID-X1患者的不同基因治疗方法,尤其侧重于淋巴样免疫重建以及改善了治疗过程和结果的进展。使用慢病毒载体和低剂量的预处理方案进行的最新临床试验表明,无论儿童还是成人,都具有出色的持续T细胞恢复能力,以及B和NK细胞。这篇综述概述了过去20年中用于治疗SCID-X1患者的不同基因治疗方法,尤其侧重于淋巴样免疫重建以及改善了治疗过程和结果的进展。使用慢病毒载体和低剂量的预处理方案进行的最新临床试验表明,无论儿童还是成人,都具有出色的持续T细胞恢复能力,以及B和NK细胞。这篇综述概述了过去20年中用于治疗SCID-X1患者的不同基因治疗方法,尤其侧重于淋巴样免疫重建以及改善了治疗过程和结果的进展。

更新日期:2020-11-27
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