Sickle cell disease in the era of precision medicine: looking to the future

Abstract

Introduction: Sickle cell anemia is a mendelian disease that is noted for the heterogeneity of its clinical expression. Because of this, providing an accurate prognosis has been a longtime quest.

Areas covered: Reviewed are the benefits and shortcomings of testing for the major modulators of the severity of disease, like fetal hemoglobin and α thalassemia, along with studies that have attempted to link genetic variation with sub-phenotypes of disease in a predictive fashion. Induced pluripotent stem cells driven to differentiate into erythroid precursor cells provide another area for potential patient-specific drug testing.

Expert opinion: Fetal hemoglobin is the strongest modulator of sickle cell anemia but simply measuring its blood levels is an insufficient means of forecasting an individual's prognosis. A more precise method would be to know the distribution of fetal hemoglobin levels across the population of red cells, an assay not yet available. Prognostic measures have been developed using genetic and other signatures, but their predictive value is suboptimal. Widely applicable assays must be developed to allow a tailored approach to using the several new treatments that are likely to be available in the near future.

Keywords: Fetal hemoglobin; GWAS; SNPs; genetic signatures; hemolysis; iPSCs; vasoocclusion.

Figure 1:. Pathophysiology of sickle cell anemia.

The sickle hemoglobin mutation (top left), codes for a β-globin gene variant, which as with normal HbA, is in solution when oxygenated. In distinction to HbA, HbS polymerizes when deoxygenated (center left). Polymerization of deoxyHbS initiates the pathophysiology of disease by injuring the sickle erythrocyte. This leads to a heterogeneously red cell population that includes adhesive cells, dense cells and irreversibly sickled cells (bottom left). These abnormal red cells damage blood vessels and cause the vasoocclusive and hemolytic components of disease. Sickle vasoocclusion (top right) provokes reperfusion injury and inflammation. It is associated with disease sub-phenotypes like acute pain episodes, acute chest syndrome and osteonecrosis. A variable portion of hemolysis occurs intravascularly (bottom right). Intravascular hemolysis depletes haptoglobin and hemopexin and liberates free heme and arginase into the plasma consuming nitric oxide leading to platelet activation, endothelial damage and inflammation. The severity of intravascular hemolysis is associated with the sub-phenotypes of pulmonary and systemic hypertension, stroke and nephropathy.

Figure 2:. Clinical trial in a test tube.

A. Global distribution of sickle cell disease and the 5 common haplotypes of the HbS globin gene. As detailed in the text, HbF levels are lowest in the Bantu haplotype, highest in the Arab-Indian haplotype and intermediate between these in the other haplotypes. B. Reprogramming somatic peripheral blood cells from patients representative of these haplotypes allows their differentiation to erythroid precursors that can reflect the HbF level of native erythrocytes. These cells might be used to test the effects of HbF-inducing therapeutics. The heat map at the lower right depicts possible outcomes of such a screen in terms of HbF levels. This output can be used to guide treatment recommendations.