Targeted approaches to induce immune tolerance for Pompe disease therapy.
Targeted approaches to induce immune tolerance for Pompe disease therapy.
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DOI：
10.1038/mtm.2015.53
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Byrne BJ
中科院分区：
文献类型：
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作者：
Doerfler PA;Nayak S;Corti M;Morel L;Herzog RW;Byrne BJ
酶和基因替代策略已经发展成为治疗Pompe病（酸性α-葡萄糖苷酶（GAA）缺乏症）的可行治疗方法。不幸的是，引入GAA和编码该酶的病毒载体可能导致有害的免疫反应，从而减弱治疗效果并影响患者安全。在处理Pompe病的酶和基因治疗的体液反应方面的临床前和临床经验，使人们对所提供治疗的免疫学后果有了更深入的了解。B细胞和t细胞调节已被证明可以有效地预防患者在酶替代治疗期间的输注相关反应，并且在基因治疗中也显示出类似的成功。诱导Pompe病体液耐受的其他技术是靶向表达或递送GAA到离散细胞类型或组织，如肠道相关淋巴组织、红细胞、造血干细胞和肝脏。通过免疫调节和基因转移来克服预先存在的免疫的研究对于实现长期疗效变得越来越重要。本文综述了治疗方法的进展以及对体液免疫反应分子机制的进一步了解，重点介绍了用于克服Pompe病的酶和基因治疗相关反应的方法。
Enzyme and gene replacement strategies have developed into viable therapeutic approaches for the treatment of Pompe disease (acid α-glucosidase (GAA) deficiency). Unfortunately, the introduction of GAA and viral vectors encoding the enzyme can lead to detrimental immune responses that attenuate treatment benefits and can impact patient safety. Preclinical and clinical experience in addressing humoral responses toward enzyme and gene therapy for Pompe disease have provided greater understanding of the immunological consequences of the provided therapy. B- and T-cell modulation has been shown to be effective in preventing infusion-associated reactions during enzyme replacement therapy in patients and has shown similar success in the context of gene therapy. Additional techniques to induce humoral tolerance for Pompe disease have been the targeted expression or delivery of GAA to discrete cell types or tissues such as the gut-associated lymphoid tissues, red blood cells, hematopoietic stem cells, and the liver. Research into overcoming preexisting immunity through immunomodulation and gene transfer are becoming increasingly important to achieve long-term efficacy. This review highlights the advances in therapies as well as the improved understanding of the molecular mechanisms involved in the humoral immune response with emphasis on methods employed to overcome responses associated with enzyme and gene therapies for Pompe disease.