Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
J Inherit Metab Dis. 2020 Jan;43(1):63-70. doi: 10.1002/jimd.12093. Epub 2019 Apr 22.
Gene therapy is currently considered as the optimal treatment for inborn errors of metabolism (IEMs), as it aims to permanently compensate for the primary genetic defect. However, emerging gene editing approaches such as CRISPR-Cas9, in which the DNA of the host organism is edited at a precise location, may have outperforming therapeutic potential. Gene editing strategies aim to correct the actual genetic mutation, while circumventing issues associated with conventional compensation gene therapy. Such strategies can also be repurposed to normalize gene expression changes that occur secondary to the genetic defect. Moreover, besides the genetic causes of IEMs, it is increasingly recognized that their clinical phenotypes are associated with epigenetic changes. Because epigenetic alterations are principally reversible, this may offer new opportunities for treatment of IEM patients. Here, we present an overview of the promises of epigenetics in eventually treating IEMs. We discuss the concepts of gene and epigenetic editing, and the advantages and disadvantages of current and upcoming gene-based therapies for treatment of IEMs.
基因治疗目前被认为是治疗先天性代谢缺陷（IEMs）的最佳方法，因为它旨在永久补偿主要的遗传缺陷。然而，新兴的基因编辑方法，如 CRISPR-Cas9，可在宿主生物体的特定位置编辑 DNA，具有更优异的治疗潜力。基因编辑策略旨在纠正实际的基因突变，同时避免与传统补偿基因治疗相关的问题。这些策略还可以重新用于使因遗传缺陷而发生的基因表达变化正常化。此外，除了 IEMs 的遗传原因外，人们越来越认识到其临床表型与表观遗传变化有关。由于表观遗传改变主要是可逆的，这可能为治疗 IEM 患者提供新的机会。在这里，我们概述了表观遗传学在最终治疗 IEMs 方面的前景。我们讨论了基因和表观遗传编辑的概念，以及当前和即将出现的基于基因的治疗方法治疗 IEMs 的优缺点。
