The role of HSA21 encoded miRNA in Down syndrome pathophysiology: opportunities in miRNA-targeted pharmacotherapy and diagnosis of the Down syndrome

Trisomy 21 is the most prevalent aneuploidy disorder among live-born children worldwide. It results from the presence of an extra copy of chromosome 21 which leads to a wide spectrum of pathophysiological abnormalities and intellectual disabilities. Nevertheless human chromosome 21 (HSA21) possess protein non-coding regions where HAS-21 derived-microRNA genes are transcribed from. In turn, these HSA21-derived miRNAs curb protein translation of several genes which are essential to meet memory and cognitive abilities. From the genetics and molecular biology standpoints, dissecting the mechanistic relationship between DS pathology/symptoms and five chromosome 21-encoded miRNAs including miR-99a, let-7c, miR-125b-2, miR-155 and miR-802 seems pivotal for unraveling novel therapeutic targets. Recently, several studies have successfully carried out small molecule inhibition of miRNAs function, maturation, and biogenesis. One might assume in the case of DS trisomy, the pharmacological inhibition of these five overexpressed miRNAs might open new avenues for amelioration of the DS symptoms and complications. In this review, we primarily elucidated the role of HSA21-encoded miRNAs in the DS pathology which in turn introduced and addressed important therapeutic targets. Moreover, we reviewed relevant pharmaceutical efforts that based their goals on inhibition of these pathological miRNAs at their different biogenesis steps. We have also discussed the challenges that undermine and question the reliability of miRNAs as none-invasive biomarkers in prenatal diagnosis.