Immunological barriers to haematopoietic stem cell gene therapy.
Immunological barriers to haematopoietic stem cell gene therapy.
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DOI：
10.1038/s41577-022-00698-0
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发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Nakauchi H
中科院分区：
文献类型：
--
作者：
Charlesworth CT;Hsu I;Wilkinson AC;Nakauchi H
使用造血干细胞(HSCs)的细胞和基因治疗体现了再生医学的变革潜力。最近涉及自体造血干细胞移植(HSCT)的基因治疗的临床成功证明了基因工程在这种干细胞类型中治愈疾病的潜力。随着CRISPR基因编辑技术、体外扩增造血干细胞的方法学和非遗传毒性调节方案的最新进展，基于造血干细胞的基因治疗的临床适应症范围有望显著扩大。然而，需要克服重大的免疫学挑战。这些挑战包括对基因治疗试剂的预先存在的免疫，对通过基因工程引入HSC的新抗原的免疫反应，以及与下一代和现成的HSC产品相关的独特挑战。通过在这篇综述中综合这些因素，我们希望鼓励更多的研究来解决与当前和下一代基于HSC的基因治疗相关的免疫学问题，以帮助实现该领域的全部潜力。要实现造血干细胞基因工程的全部潜力，使其具有广泛的临床适应症，必须克服实质性的免疫学挑战。这些反应包括对基因治疗试剂的先天和获得性免疫反应，以及对基因工程细胞表达的新抗原的获得性免疫反应。
Cell and gene therapies using haematopoietic stem cells (HSCs) epitomize the transformative potential of regenerative medicine. Recent clinical successes for gene therapies involving autologous HSC transplantation (HSCT) demonstrate the potential of genetic engineering in this stem cell type for curing disease. With recent advances in CRISPR gene-editing technologies, methodologies for the ex vivo expansion of HSCs and non-genotoxic conditioning protocols, the range of clinical indications for HSC-based gene therapies is expected to significantly expand. However, substantial immunological challenges need to be overcome. These include pre-existing immunity to gene-therapy reagents, immune responses to neoantigens introduced into HSCs by genetic engineering, and unique challenges associated with next-generation and off-the-shelf HSC products. By synthesizing these factors in this Review, we hope to encourage more research to address the immunological issues associated with current and next-generation HSC-based gene therapies to help realize the full potential of this field. To realize the full potential of genetic engineering of haematopoietic stem cells for a broad range of clinical indications, substantial immunological challenges must be overcome. These include innate and adaptive immune responses to gene-therapy reagents and adaptive immune responses to neoantigens expressed by genetically engineered cells.
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