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。

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.