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Updated: Aug 22, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNA hypo-methylating agents and sickle cell disease
Yogen Saunthararajah1, Donald Lavelle, Joseph DeSimone
1University of Illinois at Chicago, 900 S Ashland Avenue, Chicago, IL 60607-7173, USA. yogen@uic.edu
Abstract:
Fetal haemoglobin (HbF, alpha2) decreases polymerization of sickle haemoglobin (HbS) and high levels correlate with decreased morbidity and mortality in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is the pharmacologic reactivation of HbF. Silencing of the globin (HbF) gene is associated with DNA methylation. The cytosine analogues 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) hypomethylate DNA by inhibiting DNA methyl-transferase. In clinical trials, 5-azacytidine and decitabine have demonstrated the greatest efficacy in HbF reactivation. Clinical development of these drugs has been delayed by concerns regarding the carcinogenic potential of 5-azacytidine. Furthermore, controversy regarding DNA hypomethylation versus more generic cytotoxic effects as the mechanism of action suggested that other cytotoxic/cytostatic agents might be as effective. Additional preclinical data and clinical studies of decitabine have tempered many safety concerns and have confirmed that DNA hypomethylation is the mechanism of action. Pharmacologic reactivation of HbF through DNA hypomethylation holds promise as an effective disease modifying intervention for patients with SSD. Larger studies are required to confirm safety and effectiveness with chronic use.
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