MicroRNAs diferencialmente expressos induzidos pela hidroxiureia em pacientes com anemia falciforme e seus efeitos nos níveis de hemoglobina fetal (HbF): uma revisão sistemática

Abstract

Sickle cell anemia (SCA) is a recessive homozygous monogenic disease, which leads to the formation of a variant hemoglobin (HbS). Hydroxyurea (HU) has been the most widely used drug in thetreatment of sickle cell diseases (SCD) since 1998, especially due to its ability to increase fetal hemoglobin (HbF) levels, which improves the clinical condition of patients by reducing microvascular occlusion episodes and hemolysis. However, there is significant variability in clinical response among patients using HU, and HbF levels in individuals on the drug vary greatly. The molecular mechanism of action of HU in inducing HbF is not fully understood, but regulation via microRNAs appears to contribute to this variability. Therefore, a systematic review was conducted to select primary studies that identified differentially expressed miRNAs induced by HU in SCA patients, as well as their association with increased HbF levels. The Cochrane Handbook for Systematic Reviews of Interventions recommendations were followed, with results reported according to PRISMA 2020 guidelines and searches conducted in MEDLINE/PubMED, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Scopus, and Web of Science databases. A total of 64 articles were retrieved, and studies were selected if they included individuals homozygous for SCA who were at some point under HU treatment, with measurements of HbF and miRNAs post-treatment. Ultimately, four original studies were included, and data extraction and analysis revealed miRNAs consistently found in two or more studies: miR-29a, miR-148a, miR-130b, miR-494, miR-210, and miR-223, which were identified as differentially expressed (either over expressed or under expressed) in samples from individuals post-HU treatment. Literature data suggest that differentially expressed miRNAs in SCA individuals treated with HU may contribute to variability in HbF response, but current evidence is insuficiente to support this association. Due to heterogeneity among primary studies and the lack of statistical methods to adjust analyses for intrinsicand extrinsic confounding factors in patients, it is still nuclear whether differentially expressed miRNAs have prognostic value in SCA patients treated with HU.