Gene Therapy for SCID-X1 using a self-inactivating (SIN) gammaretroviral vector
使用自失活 (SIN) 伽马逆转录病毒载体进行 SCID-X1 基因治疗
基本信息
- 批准号:8719920
- 负责人:
- 金额:$ 60.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-01 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse eventAdverse reactionsAgeAllogenicArchivesB-LymphocytesBiological AssayCD3 AntigensCell CountCell Cycle KineticsCellsClinicalCytokine ReceptorsDefectDetectionDevelopmentDiagnosisDiseaseDonor personEmigrantExcisionFamilyFlow CytometryGene TransferGenesGrowth and Development functionHIVHematological DiseaseHematopoietic Stem Cell TransplantationIL2RG geneImmuneInborn Genetic DiseasesIncidenceIndividualInfectionInfusion proceduresInsertional MutagenesisLifeLinkLymphocyte FunctionLymphoidMalignant NeoplasmsMeasuresMedicalNatural Killer CellsOutcomeOutcome StudyPatientsPhasePhenotypePrincipal InvestigatorProceduresProteinsReceptors, Antigen, B-CellRecoveryRegulatory T-LymphocyteRiskSafetySamplingSevere Combined ImmunodeficiencySiblingsSiteSomatic Gene TherapySurrogate MarkersT-LymphocyteTestingToxic effectTransplantationVaccinationVirusXenograft Modelcellular transductionfollow-upgene therapygraft vs host diseaseinclusion criteriaindexinginternal controlleukemianext generationprimary outcomepromoterpublic health relevancereconstitutionresearch clinical testingresponsesuccesstherapy designtherapy resistantvector
项目摘要
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.
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。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Critical variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency.
影响用于治疗 X 连锁严重联合免疫缺陷的自失活 γ-逆转录病毒载体的临床级生产的关键变量。
- DOI:10.1038/gt.2012.37
- 发表时间:2012
- 期刊:
- 影响因子:5.1
- 作者:vanderLoo,JCM;Swaney,WP;Grassman,E;Terwilliger,A;Higashimoto,T;Schambach,A;Hacein-Bey-Abina,S;Nordling,DL;Cavazzana-Calvo,M;Thrasher,AJ;Williams,DA;Reeves,L;Malik,P
- 通讯作者:Malik,P
Curing genetic disease with gene therapy.
通过基因疗法治愈遗传病。
- DOI:
- 发表时间:2014
- 期刊:
- 影响因子:0
- 作者:Williams,DavidA
- 通讯作者:Williams,DavidA
Scale-up and manufacturing of clinical-grade self-inactivating γ-retroviral vectors by transient transfection.
- DOI:10.1038/gt.2011.102
- 发表时间:2012-03
- 期刊:
- 影响因子:5.1
- 作者:
- 通讯作者:
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DAVID A WILLIAMS其他文献
DAVID A WILLIAMS的其他文献
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Gene therapy targeting BCL11A to induce fetal hemoglobin and reduce sickle hemoglobin in patients with Sickle Cell Disease
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10179447 - 财政年份:2017
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Gene therapy targeting BCL11A to induce fetal hemoglobin and reduce sickle hemoglobin in patients with Sickle Cell Disease
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