The Role of miRNAs as Therapeutic Tools in Sickle Cell Disease.

Cyril Cyrus

doi:10.3390/medicina57101106

Abstract

Background and Objectives: Sickle cell disorder (SCD) is a paradigmatic example of a complex monogenic disorder. SCD is characterized by the production of abnormal hemoglobin, primarily in the deoxygenated state, which makes erythrocytes susceptible to intracellular hemoglobin polymerization. Functional studies have affirmed that the dysregulation of miRNAs enhances clinical severity or has an ameliorating effect in SCD. miRNAs can be effectively regulated to reduce the pace of cell cycle progression, to reduce iron levels, to influence hemolysis and oxidative stress, and most importantly, to increase γ-globin gene expression and enhance the effectiveness of hydroxyurea. Results: This review highlights the roles played by some key miRNAs in hemoglobinopathies, especially in hematopoiesis, erythroid differentiation, and severity of anemia, which make miRNAs attractive molecular tools for innovative therapeutic approaches. Conclusions: In this era of targeted medicine, miRNAs mimics and antagomirs may be promising inducers of HbF synthesis which could ameliorate the clinical severity of SCD.

Highlights

Sickle cell disorder (SCD), characterized by the production of abnormal hemoglobin, is a paradigmatic example of a monogenic disorder
The discovery of microRNAs in the mid-90s has changed the dogma of gene expression regulation [10]. miRNAs, an endogenously initiated non-coding class of short RNAs (~22-nt long), are transcribed as precursor molecules that are eventually cleaved by the Dicer and Drosha endoribonucleases [11]. miRNAs post-transcriptionally form a miRNA-mediated silencing complex to inhibit target gene expression, via either translational repression by directly binding to mRNAs, or degradation of target mRNAs by cleavage [11]. miRNAs have been found to play a quintessential role in the regulation of biological processes categorized under epigenetic regulatory mechanisms, such as chromatin-remodeling, proliferation, differentiation, development, homeostasis, and apoptosis [12,13]
The reticulocyte miRNA expression profiling performed in SCD patients with high and low HbF levels identified miRNA-144 to be highly differentially expressed in hemoglobinopathies [2]. SCD (HbSS) cells [29]

Summary

Introduction

Sickle cell disorder (SCD), characterized by the production of abnormal hemoglobin, is a paradigmatic example of a monogenic disorder. Hemolysis and anemia in SCD can initiate an erythropoietin response and stress erythropoiesis [31], which triggers the expression of the erythropoietin-dependent GATA-1 gene, and in sickle red cell progenitors, an increased generation of miRNA-144 [32]. The reticulocyte miRNA expression profiling performed in SCD patients with high and low HbF levels identified miRNA-144 to be highly differentially expressed in HbSS cells [29]. MiRNA-320 plays an important role in down-regulating its target gene, CD71, and persistently high CD71 levels in HbSS cells are associated with modest expression of miRNA-320 [15]. The overexpression of the erythropoiesis marker CD71 is reported in many malignancies, and miRNA-320-mediated inhibition of CD71 expression presents a novel treatment strategy to reduce the pace of cell cycle progression and maintain iron levels [15]

Let-7 Family

1.11. Other miRNAs

Findings

Conclusions