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.

Keywords: Epigenetic; Fetal hemoglobin; Sickle cell disease; Therapy.

Figure 1. Polymerization of deoxy sickle hemoglobin (HbS) drives the multi-organ cascade of SCD pathophysiology

Fetal hemoglobin (HbF), by blocking this polymerization, can interdict essentially all manifestations of disease, illustrated by the natural genetic experiment of hereditary persistence of fetal hemoglobin expression, and a model for drug development efforts to emulate. By contrast to HbF, normal adult hemoglobin (HbA, β-chains) can participate in polymerization. We published a variation of this figure in Molokie et al, PLoS Medicine 2017.

Figure 2. HbF induction requires chromatin remodeling, including DNA hypomethylation, of the HbF gene locus (HBG)

Bone marrow stress, e.g., from cytotoxic drugs such as hydroxyurea, can create such remodeling during the recovery phase by surviving erythroid precursors. An alternative approach is to remodel the HbF locus directly, e.g., by directly inhibiting repressing epigenetic enzymes. The relative efficiencies of these approaches are illustrated by the greater HbF increases produced in the same non-human primates or patients by decitabine ~0.2 mg/kg 2X/week, versus hydroxyurea ~20 mg/kg daily. That is, the molar amount of decitabine administered per week is <1/1000th the amount of hydroxyurea administered per week.