Gene Therapy Approaches for Primary Immunodeficiencies

原发性免疫缺陷的基因治疗方法

• 批准号: 6681511
• 负责人: Fabio Candotti
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6681511
• 关键词: CD34 molecule; Retroviridae; Wiskott Aldrich syndrome; clinical trials; disease /disorder prevention /control; gene therapy; genetic manipulation; graft versus host disease; hematopoietic stem cells; homologous transplantation; human subject; human therapy evaluation; immunodeficiency; immunogenetics; patient oriented research; severe combined immunodeficiency; technology /technique development; tissue /cell culture; transfection /expression vector; transplantation immunology

Inherited disorders of immunity are unique models that allow studying the role of specific genes and molecules in the development on the human immune system. Many of these diseases are currently only curable with allogeneic bone marrow transplantation, an intensive form of therapy with potential serious complications and that often results in only incomplete reconstitution of immunity. For those forms of immunodeficiency caused by a known genetic defect, gene therapy could therefore represent a valid alternative approach. Once proven feasible for inherited immunodeficiencies, it is likely that similar gene-based approach targeting the hematopoietic stem cell can be applied to the prevention and/or treatment of secondary forms of immunodeficiency such as that caused by HIV-1 infection. We are carrying out a clinical gene therapy trial to attempt the cure of a form of inherited immunodeficiency due to genetic defects of the adenosine deaminase gene. A strong selective advantage of gene-corrected cells is expected in this disease, which should facilitate the outcome of the procedure. In this trial, CD34+ hematopoietic progenitor cells are collected from affected patients, corrective gene transfer is performed in vitro, and the cells are returned to the patients. Immunologic follow-up will reveal if this procedure can restore the immune responses of treated patients. This trial is also comparing two different retroviral vectors with the aim of identifying the optimal vehicle for gene transfer in human hematopoietic stem cells. We have also developed pre-clinical models of gene therapy for another immunodeficiency called Wiskott-Aldrich syndrome. In these experiments, we have shown that vectors based on retroviruses can be used to correct the responsible genetic defect and to express the missing or mutated protein in cells obtained from affected patients. Work in animal models is now planned to verify in vivo safety and efficacy of the gene therapy approaches.

免疫的遗传疾病是允许研究特定基因和分子在人类免疫系统发育中的作用的独特模型。这些疾病中的许多目前只能通过同种异体骨髓移植，这是一种严重的严重并发症的密集型治疗形式，这通常只会导致免疫力重新建立。因此，对于由已知遗传缺陷引起的免疫缺陷形式，基因治疗可能代表有效的替代方法。一旦被证明是可行的，可用于遗传的免疫缺陷，靶向造血干细胞的基于基因的类似方法可以应用于预防和/或治疗次要形式的免疫缺陷，例如由HIV-1感染引起的免疫缺陷。我们正在进行一项临床基因治疗试验，以尝试治愈由于腺苷脱氨酶基因的遗传缺陷而导致的一种遗传性免疫缺陷。在该疾病中，预计被基因校正细胞具有强大的选择性优势，这应该促进该过程的结果。在这项试验中，从受影响的患者中收集CD34+造血祖细胞，在体外进行矫正基因转移，并将细胞返回给患者。免疫随访将揭示此过程是否可以恢复治疗患者的免疫反应。该试验还比较了两个不同的逆转录病毒载体，目的是确定人类造血干细胞中基因转移的最佳载体。我们还为另一种称为Wiskott-Aldrich综合征的免疫缺陷开发了基因治疗前临床模型。在这些实验中，我们已经表明，基于逆转录病毒的载体可用于纠正负责任的遗传缺陷，并在受影响的患者获得的细胞中表达缺失或突变的蛋白质。现在，计划在动物模型中进行研究，以验证基因治疗方法的体内安全性和功效。