Gene Therapy Approaches for Primary Immunodeficiencies

原发性免疫缺陷的基因治疗方法

• 批准号: 6830363
• 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/6830363
• 关键词: HIV infections; Retroviridae; Wiskott Aldrich syndrome; biotechnology; clinical trials; developmental immunology; disease /disorder prevention /control; functional /structural genomics; gene expression; gene targeting; gene therapy; genetic manipulation; hematopoietic stem cells; human subject; human therapy evaluation; immunogenetics; inborn immunodeficiency; patient oriented research; protein quantitation /detection; technology /technique development; tissue /cell culture; transfection /expression vector

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. In clinical trials for a form of inherited immunodeficiency due to genetic defects of the adenosine deaminase gene using gene transfer into peripheral blood lymphocytes, we have observed a long-term persistance and expression of the transferred gene for over 10 years. In another clinical trial attempting the correction of hematopoietic stem cells, four patients were enrolled and received treatment which did not result in clinical benefit. Plans are being made to modify the treatment strategy and improve the efficacy of the procedure. 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. In other experiments, in vitro and in vivo pre-clinical studies have been performed to verify safety and feasibility of genetc correction as treatment modality for IL-12R beta1 deficiency, an immunodeficiency that exposes affected patients to salmonella and mycobacteria infections.

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。在临床试验中，由于使用基因转移到外周血淋巴细胞中的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形式，我们观察到了10年以上转移基因的长期持久性和表达的长期持久性和表达。在试图纠正造血干细胞的另一项临床试验中，入学并接受了四名患者，这并未导致临床益处。正在制定修改治疗策略并提高程序功效的计划。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。在其他实验中，已经进行了体外和体内临床前研究，以验证GenETC校正作为IL-12R Beta1缺乏症的治疗方式的安全性和可行性，这是一种免疫缺陷，可将影响患者暴露于沙门氏菌和分枝杆菌感染。