Gene Therapy Approaches for Primary Immunodeficiencies

原发性免疫缺陷的基因治疗方法

• 批准号: 6555997
• 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/6555997
• 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; human tissue; immunodeficiency; immunogenetics; patient oriented research; severe combined immunodeficiency; technology /technique development; tissue /cell culture; transfection /expression vector; transplantation immunology

Primary immunodeficiency diseases represent an unique model to study the development on the human immune system. For several of these diseases, the only currently available therapy is allogeneic bone marrow transplantation, which may result in incomplete reconstitution of immunity and may be associated with severe graft versus host reactions. Genetic correction of autologous hematopoietic stem cells would thus represent a beneficial alternative form of treatment for those immunodeficiencies of known genetic origin. Once proven feasible for inherited immunodeficiencies, it is expected that similar genetic manipulations of hematopoietic stem cells can be applied to the prevention and/or treatment of secondary forms of immunodeficiency such as that caused by HIV-1 infection. We have developed pre-clinical models of gene therapy for two immunodeficiencies called X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich syndrome. In these experiments, vectors based on retroviruses are being used to correct the responsible genetic aberration and to express the missing or mutated protein in cells obtained from affected patients. Animal models are available for both immunodeficiencies, which allows experiments of genetic correction of bone marrow hematopoietic progenitors. These experiments are performed to verify in vivo safety and efficacy of the gene therapy approaches. A clinical gene therapy trial in ongoing under this project to attempt the cure of another immunodeficiency called adenosine deaminase deficiency. 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.

原发性免疫缺陷疾病代表了研究人类免疫系统发展的独特模型。对于其中几种疾病，目前唯一可用的治疗是同种异体骨髓移植，这可能导致免疫的重新建立不完全，并且可能与严重的移植物与宿主反应有关。因此，自体造血干细胞的遗传校正将代表一种有益的替代形式的治疗形式，用于已知遗传起源的免疫缺陷。一旦被证明是可行的，可用于遗传的免疫缺陷，预计可以将类似的造血干细胞的遗传操作应用于预防和/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。我们已经开发了两种称为X连锁严重合并免疫缺陷（X-SCID）和Wiskott-Aldrich综合征的免疫缺陷的基因治疗前临床模型。在这些实验中，基于逆转录病毒的载体用于纠正负责任的遗传像差，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。动物模型可用于两种免疫缺陷，允许对骨髓造血祖细胞的遗传校正实验。进行这些实验以验证基因治疗方法的体内安全性和功效。该项目正在进行的一项临床基因治疗试验试图治愈另一种称为腺苷脱氨酶缺乏症的免疫缺陷。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。