Fetal Hemoglobin Induction by Epigenetic Drugs

Abstract

Fetal hemoglobin (HbF) inhibits the root cause of sickle pathophysiology, sickle hemoglobin polymerization. Individuals who naturally express high levels of HbF beyond infancy thus receive some protection from sickle complications. To mimic this natural genetic experiment using drugs, one guiding observation was that HbF is increased during recovery of bone marrow from extreme stress. This led to evaluation and approval of the cytotoxic (cell killing) drug hydroxyurea to treat sickle cell disease. Cytotoxic approaches are limited in potency and sustainability, however, since they require hematopoietic reserves sufficient to repeatedly mount recoveries from stress that destroys their counterparts, and such reserves are finite. HbF induction even by stress ultimately involves chromatin remodeling of the gene for HbF (HBG), therefore, a logical alternative approach is to directly inhibit epigenetic enzymes that repress HBG-implicated enzymes include DNA methyltransferase 1, histone deacetylases, lysine demethylase 1, protein arginine methyltransferase 5, euchromatic histone lysine methyltransferase 2 and chromodomain helicase DNA-binding protein 4. Clinical proof-of-principle that this alternative, noncytotoxic approach can generate substantial HbF and total hemoglobin increases has already been generated. Thus, with continued careful attention to fundamental biological and pharmacologic considerations (reviewed herein), there is potential that rational, molecular-targeted, safe and highly potent disease-modifying therapy can be realized for patients with sickle cell disease, with the accessibility and cost-effective properties needed for world-wide effect.

Sickle Cell Disease: Advances in Treatment

“…94 Researchers have proposed that interference with or depletion of DNMT1 might prevent the switchoff of hemoglobin F production. [95][96][97][98][99][100] The drug decitabine and its prodrug 5azacytidine have been found to deplete DNMT1 levels. 101 In animals, 5-azacytidine produced increases in hemoglobin F levels up to 20 times those produced by hydroxyurea, even in animals that derived minimal benefit from hydroxyurea by being poor responders.…”

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

“…The inhibition appears to proceed through the free radical nitroxide metabolite of hydroxyurea, which quenches the tyrosyl free radical at the active site of the M2 protein subunit of the enzyme [ 190 , 191 ]. Hydroxyurea is also used in the treatment of sickle cell anemia and thalassemia intermedia, by increasing fetal hemoglobin synthesis which reduces the polymerization of sickle cell hemoglobin and the level of RBC transfusions, respectively [ 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 ]. Hydroxyurea has been recently identified as a natural product with possible antiviral and other applications [ 201 , 202 , 203 ].…”

A new target for fetal hemoglobin reactivation

“…A logical approach to increase HbF for therapy of the hemoglobinopathies is to intervene with the epigenetic repression mechanism that executes the switch from HbF to adult hemoglobin (HbA; a2g2). [3][4][5] In this issue, the Ginder laboratory has identified a specific co-repressor, MBD2-NURD, that is responsible for silencing g-globin expression in adult erythroid cells and has delineated critical amino acid residues within the MBD2 protein that recruit the co-repressor containing the epigenetic-modifying enzymes that mediate silencing. 6 The identification of these sites of recruitment should allow the identification and development of new drugs that interfere with these interactions to alleviate gene repression and increase gglobin expression in adult erythroid cells and that, due to the mild phenotype of MBD2 -/mice, 7 would be expected to have acceptable side-effects in patients.…”

“…13,14 Pharmacological inhibitors of these enzymes increase g-globin expression in various cell culture, mouse, and nonhuman primate model systems, often to impressive levels that would be predicted to provide therapeutic benefits to SCD and β-thalassemia patients. [3][4][5] The major issue hindering use of these drugs in patients are dose-limiting hematologic side-effects that include neutropenia, thrombocytopenia, or thrombophilia.…”

“…Precision medicine is becoming the mainstream of future medicine. It has been implemented in the clinical practice in acute myeloid leukemia (AML), 5 and myeloproliferative…”