Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, MSC1456, Bldg 10, Rm 5-3750, Bethesda, MD 20892-1456, USA.
National Human Genome Research Institute, NIH, 10 Center Dr, MSC1611, Bldg 10, Rm 10C-103, Bethesda, MD 20892-1611, USA.
Hematol Oncol Clin North Am. 2022 Aug;36(4):627-645. doi: 10.1016/j.hoc.2022.05.001. Epub 2022 Jun 27.
The earliest conceptual history of gene therapy began with the recognition of DNA as the transforming substance capable of changing the phenotypic character of a bacterium and then as the carrier of the genomic code. Early studies of oncogenic viruses that could insert into the mammalian genome led to the concept that these same viruses might be engineered to carry new genetic material into mammalian cells, including human hematopoietic stem cells (HSC). In addition to properly engineered vectors capable of efficient safe transduction of HSC, successful gene therapy required the development of efficient materials, methods, and equipment to procure, purify, and culture HSC. Increased understanding of the preparative conditioning of patients was needed to optimize the engraftment of genetically modified HSC. Testing concepts in pivotal clinical trials to assess the efficacy and determine the cause of adverse events has advanced the efficiency and safety of gene therapy. This article is a historical overview of the separate threads of discovery that joined together to comprise our current state of gene therapy targeting HSC.
基因治疗的最早概念历史始于认识到 DNA 是能够改变细菌表型特征的转化物质，然后是基因组编码的载体。对能够插入哺乳动物基因组的致癌病毒的早期研究导致了这样一种概念，即可以对这些相同的病毒进行工程改造，以便将新的遗传物质带入哺乳动物细胞，包括人类造血干细胞 (HSC)。除了能够有效安全地转导 HSC 的经过适当工程设计的载体外，成功的基因治疗还需要开发有效的材料、方法和设备来获取、纯化和培养 HSC。需要增加对患者制备条件的了解，以优化经基因修饰的 HSC 的植入。在关键临床试验中测试概念以评估疗效并确定不良事件的原因，提高了基因治疗的效率和安全性。本文是对汇集在一起构成我们目前针对 HSC 的基因治疗状态的各个发现线索的历史概述。
