Teng-Cheong Ha, Michael A Morgan, Adrian J Thrasher, Axel Schambach
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引用次数: 0
Abstract
Severe combined immunodeficiency (SCID) encompasses rare primary immunodeficiency disorders characterized by deficient T-cell development, which leads to a severely compromised immune system and susceptibility to life-threatening infections. Among SCID subtypes, IL7RA-SCID is caused by mutations in the interleukin 7 receptor alpha chain (IL7RA) and represents a significant subset of patients with limited treatment options. This study investigated the efficacy of a self-inactivating (SIN) alpharetroviral vector (ARV) engineered to deliver a codon-optimized IL7RA cDNA to restore T-cell development in Il7r-knockout mice. We compared the elongation factor 1 alpha short (EFS) promoter and the lymphoid-restricted Lck promoter for their ability to drive IL7RA expression and found that the EFS promoter enabled robust and sustained IL7RA expression that led to the functional rescue of T-lymphopoiesis in vitro and in vivo. Conversely, though effective in vitro, the Lck promoter failed to produce viable T-cell populations in vivo. Our results highlight the potential of using SIN-ARVs as a gene therapy (GT) strategy for treating IL7RA-SCID. Importantly, sustained production of T-lymphocytes was found in both primary and secondary transplant recipient animals with no adverse effects, supporting the safety and feasibility of this approach. Overall, this study provides valuable insights into the development of GT for IL7RA-SCID and underscores the clinical potential of an EFS-driven SIN-ARV to restore IL7RA-deficient immune function.
严重联合免疫缺陷症(SCID)是一种罕见的原发性免疫缺陷疾病,其特点是 T 细胞发育不全,导致免疫系统严重受损,容易受到危及生命的感染。在SCID亚型中,IL7RA-SCID是由白细胞介素7受体α链(IL7RA)突变引起的,是治疗方案有限的重要患者亚型。本研究调查了一种自失活(SIN)α逆转录病毒载体的疗效,该载体被设计为递送经过密码子优化的IL7RA cDNA,以恢复IL7RA基因敲除小鼠的T细胞发育。我们比较了α短伸长因子(EFS)启动子和淋巴限制性Lck启动子驱动IL7RA表达的能力,发现EFS启动子能使IL7RA得到稳健而持续的表达,从而在体外和体内实现T淋巴细胞生成的功能性拯救。相反,Lck 启动子虽然在体外有效,但在体内却不能产生有活力的 T 细胞群。我们的研究结果凸显了使用 SIN-逆转录病毒载体作为基因治疗(GT)策略治疗 IL7RA-SCID 的潜力。重要的是,在初次和二次移植受体动物中都发现了T淋巴细胞的持续生成,且无不良反应,这支持了这种方法的安全性和可行性。总之,这项研究为IL7RA-SCID基因疗法的开发提供了宝贵的见解,并强调了EFS驱动的SIN-alpharetroviral载体恢复IL7RA缺陷免疫功能的临床潜力。
期刊介绍:
Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.