Prospects for early investigational therapies for sickle cell disease

Figures & data

Figure 1. Pathophysiology of Sickle Cell Disease (SCD). SCD is characterized by the production of hemoglobin S (HbS) in red blood cells (RBC). Hb S polymerizes when deoxygenated, causing the cells to become rigid and adopt a sickled state, as well as making cells more fragile and susceptible to rupture (hemolysis). Increasing levels of fetal hemoglobin (HbF) in RBC can reduce hemoglobin polymerization and therefore RBC sickling and hemolysis. Intravascular hemolysis has significant consequences; hemoglobin (Hb) released into the plasma results in endothelium-derived nitric oxide (NO) depletion in the blood vessel and the release of the toxic Hb product, hemin. Red cell lysis also increases plasma arginase, consequently limiting the availability of the substrate for NO synthesis, L-arginine. Oxidative Hb reactions, as well as reduced NO bioavailability and hemin production, contribute significantly to vascular oxidative stress and endothelial cell activation. Activated endothelium produces inflammatory cytokines and expresses adhesion molecules on its surface, resulting in leukocyte capture, and RBC and platelet adhesion to the vascular wall. Inflammatory mediator production from activated platelets, leukocytes and endothelial cells results in the inflammatory state that is associated with SCD and that drives recurrent vaso-occlusive processes, which result from leukocyte and RBC adhesion to the endothelium, occasioning reduced blood flow, diminished oxygen concentrations, consequent red cell sickling and eventually the occlusion of vessels. In a vicious cycle, chronic vascular inflammation and recurrent vaso-occlusive processes occur, causing hypoxia/reperfusion injury and resulting in further oxidative stress. Additionally, hypoxia triggers the synthesis of pro-angiogenic factors that results in the upregulation of angiogenesis and further endothelial activation and inflammation. Currently early investigational therapies under development for SCD use a pathophysiological-based approach to abolish or reduce one or more of the mechanisms that contribute to this disease’s complex pathophysiology.

Table 1. Early investigational therapies for sickle cell disease and their pathophysiological targets.

Target pathophysiological mechanism	Drug class/drug under early investigation	Examples	Mechanism of action	Ref.
HbS polymerization/red cell sickling	Thalidomide derivatives/hybrids	Pomalidomide, lenalidomide compounds 4c/4d,	Immunomodulators that elevate HbF, inhibiting HbS polymerization. Also have anti-inflammatory effects.	[7,8]
	Histone deacetylase (HDAC) inhibitor agents	Sodium butyrate azacitidine decitabine,	Elevation of γ- globin expression and, therefore, HbF production.	[9]
	Allosteric effectors of Hb	5HF (Aes-103) TD-1,	Increase the oxygen affinity of Hb, reducing polymerization and RBC sickling.	[10,40]
Endothelial activation/inflammation	Statins	Simvastatin atorvastatin,	Reduction of endothelial activation and anti-inflammatory effects.	[20]
	TNF-α antagonists	Etanercept,	Reduction of endothelial activation and anti-inflammatory effects.	[23]
	Invariant natural killer T (iNKT) cell depletants	NKTT120,	Monoclonal antibodies that deplete iNKT cells, reducing inflammatory molecule release.	[21]
	A2AR agonists	Ragadenoson,	Decrease iNKT-cell activation and reduce inflammation.	[22]
Cell adhesion	Selectin inhibitors	Rivipansel (GMI-1070) SelG1,	Inhibition of leukocyte/endothelial/platelet adhesion molecules resulting in reduced blood cell adhesion to the blood vessel wall.	[14,16]
	Low-molecular-weight heparin		L-selectin/P-selectin inhibitor; inhibition of leukocyte/endothelial/platelet adhesion molecules resulting in reduced blood cell adhesion to the vessel wall.	[16]
	Intravenous gamma globulin (IVIG)		Inhibition of leukocyte activation and recruitment.	[17]
	Poloxamer 188		Non-ionic surfactant, reduces blood viscosity and cell adhesion.	[18]
Hypoxia	Pegylated Hb-based carbon monoxide carriers.	MP4CO Sanguinate^TM,	Release of anti-inflammatory carbon monoxide and delivery of oxygen to hypoxic tissues.	[24] NCT01374165
Platelet activation/activity	ADP receptor antagonists	Prasugrel	Inhibit ADP-mediated platelet activation and platelet-leukocyte aggregate formation.	[26]
	αIIbβ3-integrin inhibitors	Eptifibatide	Inhibition of αIIbβ3 integrin-dependent platelet activation and aggregation.	[25]
Hemolysis	Hemoglobin/heme scavengers	Haptoglobin hemopexin, hE-Hb-B10 A1M,	Binding and clearance of plasma hemoglobin or its products.	[27-29]
Nitric oxide bioavailability/signaling amplification	Arginine therapy	L-arginine	Increase availability of substrate for NO synthesis.	[32]
	Phosphodiesterase inhibitors	BAY73 – 6691 (PDE9i) PF04447943 (PDE9i)	Amplification of intracellular NO signaling pathways.	[33] NCT02114203
Oxidative stress	L-Glutamine		Enhancement of nicotinamide adenine dinucleotide in sickle RBC.	[11]
Red cell dehydration	Gardos channel inhibitors	Senicapoc (ICA-17043)	Reduction of potassium leakage, decreasing cell dehydration.	[12]

Hb: Hemoglobin; NO: Nitric oxide; PDE9i: Phosphodiesterase 9 inhibitor; RBC: Red blood cell.

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