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）是一组异质性致死性遗传性疾病，其特征是T淋巴细胞功能严重减少或缺失。最常见的SCID形式是由常见细胞因子受体缺陷引起的x连锁形式（SCID- x1）。链(?c或IL-2RG)。直到最近体细胞基因治疗的出现，造血干细胞移植（HSCT）是任何形式SCID患者的唯一治疗选择。在20-25%的病例中，当有基因典型匹配的兄弟姐妹供体时，HSCT是一个非常成功的手术。对于剩下的个体，替代供体移植，主要来自匹配不相关（MUD）或单倍体相同的亲代供体，由于消融治疗的毒性、移植物抗宿主病和淋巴细胞重建不完全，一直存在问题。最近的基因转移试验证明了有效性，尽管与插入诱变有关的毒性。我们开发了一种新一代的自我失活（SIN）载体，表达由细胞内部启动子pSRS11.EFS.IL2RG控制的IL-2RG基因。在非临床研究中，pre*和研究表明，与LTR配置相比，该载体具有更低的致突变潜力。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，但没有插入突变。目前的研究是一项针对SCID-X1患者的体细胞基因治疗的i /ll期试验。纳入标准包括明确诊断为SCIDX1且无法获得HLA匹配的家庭供体的患者，以及年龄在0 ~ 3.5个月之间且缺乏HLA相同（a、B、C、DR、DQ）非亲属供体的患者，或患有活动性、治疗耐药感染或其他显著增加同种异体移植风险的医疗状况的患者。主要终点包括免疫重建，定义为输注后6个月的绝对CD3细胞bbb300 /¿l和PHA刺激指数>5，以及与基因转移过程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。

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.