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

描述(由申请人提供)：严重联合免疫缺陷(SCID)是一组不同类型的致命性遗传性疾病，其特征是T淋巴细胞功能严重降低或缺失。SCID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。链(？C或IL-2RG)。直到最近躯体基因治疗的出现，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%的病例中，当有基因匹配的同胞供体时，HSCT是一种非常成功的手术。对于其余个体，替代供者移植，主要来自匹配的无血缘关系(MUD)或单倍体相合的双亲供者，由于消融治疗、移植物抗宿主病和不完全淋巴重建的毒性而一直存在问题。最近的基因转移试验已经证明了有效性，尽管与插入突变有关的毒性。我们已经开发了一种由内部细胞启动子pSRS11.EFS.IL2RG.pre*控制的表达IL-2RG基因的新一代自失活(SIN)载体，并在非临床研究中表明该载体与LTR配置相比具有更低的诱变潜力。我们假设该载体将具有与过去试验中使用的载体类似的效果，但没有插入突变。本研究是针对SCID-X1患者的体细胞基因治疗的L/11期试验。纳入标准包括确诊为SCIDX1的患者，其中没有匹配的家庭捐赠者，并且是3.5个月大的患者和缺乏完全相同的(A，B，C，DR，DQ)无关捐赠者的患者，或者任何年龄的患者，他们患有活动性的、耐药感染或其他显著增加异基因移植风险的医疗条件。主要观察指标包括输注后6个月的免疫重建(定义为L体内CD3细胞的绝对值)和PHA刺激指数及与基因转移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部位分析研究。 公共卫生相关性(由申请者提供)：基因疗法有望治愈许多疾病，包括癌症、艾滋病毒、血液疾病和其他疾病。严重联合免疫缺陷的基因治疗是为数不多的成功文献之一，但由于20名患者中有5名患者发展为白血病，因此出现了严重的并发症。这项研究将证明一种更安全的基因治疗设计是否会在不导致白血病的情况下有效。

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.