Gene Therapy for SCID-X1 using a self-inactivating (SIN) gammaretroviral vector

描述（由申请方提供）：重度联合免疫缺陷（SCID）是一组异质性致死性遗传性疾病，其特征为T淋巴细胞功能显著降低或缺失。最常见的形式是X连锁形式（SCID-X1），由常见的细胞因子受体缺陷引起。chain（？c或IL-2 RG）。直到最近体细胞基因治疗的出现，造血干细胞移植（HSCT）为任何形式的SCID患者提供了唯一的治疗选择。在20-25%的情况下，当一个基因型匹配的同胞供体是可用的，HSCT是一个非常成功的程序。对于其余的个体，替代供体移植，主要来自匹配的无关（MUD）或单倍相合的亲本供体，由于消融治疗的毒性、移植物抗宿主病和不完全淋巴重建而存在问题。最近的基因转移试验已经证明了疗效，尽管与插入诱变有关的毒性。我们已经开发了表达由内部细胞启动子控制的IL-2 RG基因的下一代自失活（SIN）载体pSRS11.EFS.IL2RG.pre*，并在非临床研究中显示该载体与LTR构型相比具有降低的致突变潜力。我们假设该载体将具有与过去试验中使用的载体相似的功效，但没有插入诱变。本研究是对患有SCID-Xl的患者进行体细胞基因疗法的I/II期试验。入选标准包括明确诊断为SCIDX 1的患者，其中HLA匹配的家族供体不可用，并且患者年龄>3.5个月且缺乏HLA相同（A、B、C、DR、DQ）的无关供体，或者任何年龄的患者，其具有活动性、耐药性感染或显著增加同种异体移植风险的其他医学状况。主要终点包括免疫重建，定义为输注后6个月时绝对CD 3细胞>300/μ l和PHA刺激指数>15，以及与基因转移程序相关的危及生命的不良反应的发生率。我们还将进行详细的免疫重建和插入位点分析研究。 公共卫生相关性（由申请人提供）：基因治疗对许多疾病的治疗有很大的希望，包括癌症，艾滋病毒，血液病等。基因治疗严重联合免疫缺陷症是少数成功的记录之一，但由于20例患者中有5例发生白血病而产生了严重的并发症。这项研究将证明一种更安全的基因治疗设计是否有效而不引起白血病。

DESCRIPTION (provided by applicant): Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal inherited disorders characterized by a profound reduction or absence of T lymphocyte function. The most common form of SCID is an X-linked form (SCID-X1) caused by defects in the common cytokine receptor ? chain (?c or IL-2RG). Until the recent advent of somatic gene therapy, hematopoietic stem cell transplantation (HSCT) offered the only curative option for patients with any form of SCID. In the 20-25% of cases when a genotypically matched sibling donor is available, HSCT is a highly successful procedure. For the remaining individuals, alternative donor transplants, principally from matched unrelated (MUD) or haploidentical parental donors have been problematic due to toxicity from ablative therapy, graft-versus-host disease and incomplete lymphoid reconstitution. Recent gene transfer trials have documented efficacy, albeit with toxicity related to insertional mutagenesis. We have developed a next generation self-inactivating (SIN) vector expressing the IL-2RG gene controlled by an internal cellular promoter, pSRS11.EFS.IL2RG.pre* and have shown this vector to have reduced mutagenic potential compared to LTR configuration in non-clinical studies. We hypothesize that this vector will have similar efficacy to the vector used in the past trial but without insertional mutagenesis. The current study is a phase l/ll trial of somatic gene therapy for patients with SCID-X1. Inclusion criteria include patients with a definitive diagnosis of SCIDX1 in whom HLA-matched family donors are unavailable and who are either patients >3.5 months old and lack an HLA identical (A,B,C,DR,DQ) unrelated donor OR patients of any age with an active, therapy-resistant infection or other medical conditions that significantly increase the risk of allogeneic transplant. Primary endpoints include immunological reconstitution defined as absolute CD3 cells of >300/¿l and PHA stimulation index >15 at 6 months post infusion and the incidence of life-threatening adverse reactions related to the gene transfer procedure. We will also perform detailed immune reconstitution and insertion site analysis studies. PUBLIC HEALTH RELEVANCE (provided by applicant): Gene therapy holds great promise for cure of many diseases, including cancer, HIV, blood disorders, and others. Gene therapy for severe combined immunodeficiency has been one of few documented successes but has had significant complications due to development of leukemia in 5 of 20 patients. This study will prove whether a safer gene therapy design will be effective without causing leukemia.