Page 43 - 2019_09-HaematologicaMondo-web

Targeting sickle cell root-cause pathophysiology
ization. These active efforts are discussed in turn, with an emphasis on lessons learned so far and remaining open questions.
Small molecule approaches for which there are no active clinical efforts that we are aware of are not discussed here, e.g., small molecules to decrease HbS concentration by increasing RBC hydration.5,6 Methods to interdict HbS polymerization that are not based on small molecule drugs are also not discussed here, because their applica- tion in the areas of the world most affected by SCD will be difficult for reasons of infrastructure and costs, e.g., har- vesting of autologous hematopoietic stem cells, their engi- neering ex vivo, then re-infusion after myeloablative bone marrow conditioning by chemotherapy and/or radiation (gene therapy), or use of hematopoietic stem cells from immune-compatible non-SCD donors for transplant – a valuable approach in the West that has been thoroughly and recently reviewed elsewhere.7
Interdicting HbS polymerization by pharmacolog- ical induction of HbF
At the fetal stage of life, RBC contain fetal hemoglobin (HbF), an assembly of two a-globin subunits and two γ- globin subunits (a2γ2), with the γ-globin subunits being encoded by duplicated γ-globin genes (HBG2 and HBG1). During human development, the switch from HbF to HbA production begins late in fetal gestation (~ 7 months), and the typical adult pattern of <1% HbF and >90% HbA in
RBC is established by ~12 months post-conception.8,9 Several genetic polymorphisms or mutations in humans, some but not all identified, promote persistent, relatively high RBC HbF content beyond infancy. The phenotypes with particularly generous HbF levels (HbF >10%) are referred to as hereditary persistence of fetal hemoglobin (HPFH). SCD patients who co-inherit such genetic vari- ants can, in the best cases, have asymptomatic, normal life-spans.10-12 Notably, HbF has benefits even at lower dynamic ranges than seen in HPFH: HbF levels correlate continuously with fewer vaso-occlusive pain crises, less renal damage, less pulmonary hypertension, fewer strokes and longer survival.4,13-19 In short, nature has demonstrated that HbF is a highly potent modulator of SCD.20
Detailed biochemical studies have demonstrated how: the intracellular concentration of HbS is a major determi- nant of polymerization kinetics, and HbF substitution for HbS decreases this concentration.20-22 Moreover, HbF does not polymerize with deoxygenated HbS for reasons of molecular structure (the sophisticated biophysics underly- ing this have recently been reviewed in detail).5 By con- trast, HbA can polymerize with deoxygenated HbS.20-22 In short, HbF interdicts the root-cause pathophysiology of SCD. It is logical therefore to attempt to use pharmacolo- gy to recapitulate such naturally demonstrated, powerful disease modulation.23
The earliest efforts at HbF induction
The earliest efforts built on the observation that HbF is enriched in RBC produced during the recovery phase of
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.95 and Lavelle et al.23
haematologica | 2019; 104(9)
1721