Targeting sickle cell disease root-cause pathophysiology with small molecules

Abstract

The complex, frequently devastating, multi-organ pathophysiology of sickle cell disease has a single root cause: polymerization of deoxygenated sickle hemoglobin. A logical approach to disease modification is, therefore, to interdict this root cause. Ideally, such interdiction would utilize small molecules that are practical and accessible for worldwide application. Two types of such small molecule strategies are actively being evaluated in the clinic. The first strategy intends to shift red blood cell precursor hemoglobin manufacturing away from sickle hemoglobin and towards fetal hemoglobin, which inhibits sickle hemoglobin polymerization by a number of mechanisms. The second strategy intends to chemically modify sickle hemoglobin directly in order to inhibit its polymerization. Important lessons have been learnt from the pre-clinical and clinical evaluations to date. Open questions remain, but this review summarizes the valuable experience and knowledge already gained, which can guide ongoing and future efforts for molecular mechanism-based, practical and accessible disease modification of sickle cell disease.

Figure 1.

Polymerization of sickle hemoglobin drives the multi-organ cascade of sickle cell disease pathophysiology. This review examines the strategies to interdict the multi-organ cascade of sickle cell disease at its inception using small molecules that shift red blood cell precursor production from sickle hemoglobin (HbS) toward fetal hemoglobin (HbF), and small molecules that chemically modify HbS to decrease its polymerization. We published variations of this figure in Molokie et al. and Lavelle et al.

Figure 2.

Induction of fetal hemoglobin (HbF) requires chromatin remodeling, including DNA hypomethylation, of the HbF gene locus. Bone marrow stress, e.g., from cytotoxic drugs such as hydroxyurea, can create chromatin remodeling during the recovery phase of surviving erythroid precursors. An alternative approach is to remodel the hemoglobin F (HbF) gene locus (HBG) directly, e.g., by directly inhibiting/repressing epigenetic enzymes. Enzymes shown are those known to be recruited by BCL11A, TR2 or TR4 (EHMT2 and PRMT5 are not reported participants in the BCL11A/TR2/TR4 hub). 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 twice weekly versus hydroxyurea ~20 mg/kg daily. That is, the molar amount of decitabine administered per week is <1/1000^th the amount of hydroxyurea administered per week. We published variations of this figure in Molokie et al. and Lavelle et al.