Precision Medicine and Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is characterized by variable clinical outcomes, with some patients suffering life-threatening complications during childhood, and others living relatively symptom-free into old age. Because of this variability, there is an important potential role for precision medicine, in which particular different treatments are selected for different groups of patients. However, the application of precision medicine in SCD is limited by difficulties in identifying different prognostic groups and the small number of available treatments. The main genetic determinant of outcomes in SCD is the underlying β-globin genotype, with sickle cell anemia (HbSS) and hemoglobin SC disease (HbSC) forming the 2 major forms of the disease in most populations of African origin. Although there are clear differences in clinical outcomes between these conditions, treatments approaches are very similar, with little evidence on how to treat HbSC in particular. Other genomic information, such as the co-inheritance of α-thalassemia, or high fetal hemoglobin (HbF) levels, is of some prognostic value but insufficient to determine treatments. Precision medicine is further limited by the fact that the 2 main drugs used in SCD, penicillin and hydroxyurea, are currently recommended for all patients. Newer treatments, such as crizanlizumab and voxelotor, raise the possibility that groups will emerge who respond best to particular drugs or combinations. Perhaps the best current example of precision medicine in SCD is the selective use of blood transfusions as primary stroke prevention in children with evidence of cerebral vasculopathy. More precise treatments may emerge as we understand more about the pathology of SCD, including problems with erythropoiesis.

Population characterization of mutations for sickle cell anemia and its treatment: One step towards personalized medicine for the disease

“…Esta frecuencia diferencial en los SNPs clínicamente relevantes es importante para la personalización de los tratamientos médicos. Esta información podría ser utilizada para desarrollar políticas públicas personalizadas basadas en la información genómica de la población a la que se accede en diferentes bases de datos 16 .…”

Are we ready for new strategies to prevent stroke in children with sickle cell disease?

“…SCD is a monogenic disorder with significant phenotypic variability (3). In spite of the outstanding improvement in the comprehensive care of children with SCD in the past decades, possibility for precision medicine has been slow to develop and stroke and CVA continue to cause significant mortality and morbidity in high income countries: stroke is still one of the main causes on mortality in children under 5 years of age in children diagnosed and taken in care since birth (4) and still causes major impact in terms of general and intellectual disabilities (5).The results of De Ligt et al are in line with the most recent clinical achievements, that look for a refined precision therapy in SCD, trying to calibrate interventions and treatments, tailoring them to the individual clinical situation or to well defined subgroups of patients (6). New strategies for risk stratification of cerebral vasculopathy are, therefore, deeply warranted and studies in this field are welcomed.…”

News on sickle cell disease: Heme‐driven disordered erythropoiesis

“…Although gene therapy is upcoming for the treatment of SCD, not all patients are eligible for it. Therefore, most patients rely on classical treatments, including transfusion therapy support, EPO and hydroxyurea, and more recent drugs such as inhibitors of hemoglobin polymerization (e.g., Voxelotor) and endothelial activations (e.g., P‐selectin inhibitor), and antioxidants (e.g., l ‐glutamine) 1,5 . The use of EPO has become more widespread in the management of SCD, especially when used in conjunction with hydroxyurea—with the aim to further increase fetal hemoglobin expression.…”