OBRR/DBCD/LCH in the Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
OTAT/DPPT/HB in the Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Int J Mol Sci. 2020 May 20;21(10):3598. doi: 10.3390/ijms21103598.
MicroRNAs (miRNA) play an important role in gene expression at the posttranscriptional level by targeting the untranslated regions of messenger RNA (mRNAs). These small RNAs have been shown to control cellular physiological processes including cell differentiation and proliferation. Dysregulation of miRNAs have been associated with numerous diseases. In the past few years miRNAs have emerged as potential biopharmaceuticals and the first miRNA-based therapies have entered clinical trials. Our recent studies suggest that miRNAs may also play an important role in the pathology of genetic diseases that are currently considered to be solely due to mutations in the coding sequence. For instance, among hemophilia A patients there exist a small subset, with normal wildtype genes; i.e., lacking in mutations in the coding and non-coding regions of the gene. Similarly, in many patients with missense mutations in the gene, the genetic defect does not fully explain the severity of the disease. Dysregulation of miRNAs that target mRNAs encoding coagulation factors have been shown to disturb gene expression. Alterations in protein levels involved in the coagulation cascade mediated by miRNAs could lead to bleeding disorders or thrombosis. This review summarizes current knowledge on the role of miRNAs in hemophilia and thrombosis. Recognizing and understanding the functions of miRNAs by identifying their targets is important in identifying their roles in health and diseases. Successful basic research may result in the development and improvement of tools for diagnosis, risk evaluation or even new treatment strategies.
微小 RNA（miRNA）通过靶向信使 RNA（mRNA）的非翻译区在转录后水平上对基因表达发挥重要作用。这些小 RNA 已被证明可控制细胞生理过程，包括细胞分化和增殖。miRNA 的失调与许多疾病有关。在过去的几年中，miRNA 已成为潜在的生物制药，第一批基于 miRNA 的疗法已进入临床试验。我们最近的研究表明，miRNA 也可能在目前被认为仅由于编码序列突变引起的遗传疾病的病理学中发挥重要作用。例如，在正常野生型基因的血友病 A 患者中存在一小部分；即，在 基因的编码和非编码区域中没有突变。同样，在许多具有 基因错义突变的患者中，遗传缺陷并不能完全解释疾病的严重程度。已经表明，靶向编码凝血因子的 miRNA 可扰乱基因表达。miRNA 介导的凝血级联反应中涉及的蛋白质水平的改变可能导致出血性疾病或血栓形成。这篇综述总结了 miRNA 在血友病和血栓形成中的作用的现有知识。通过鉴定其靶标来识别和理解 miRNA 的功能对于确定它们在健康和疾病中的作用非常重要。成功的基础研究可能会导致开发和改进用于诊断、风险评估甚至新的治疗策略的工具。
