Emerging Science of Hydroxyurea Therapy for Pediatric Sickle Cell Disease

Hydroxyurea is the sole approved pharmacologic therapy for sickle cell disease (SCD). Higher fetal hemoglobin (HbF) levels diminish de-oxygenated sickle globin polymerization in vitro and clinically reduce the incidence of disease morbidities. Clinical and laboratory effects of hydroxyurea largely result from induction of HbF expression, though to a highly variable extent. Baseline and hydroxyurea-induced HbF expression are both inherited complex traits. In children with SCD, baseline HbF remains the best predictor of drug-induced levels, but accounts for only portion of the induction. A limited number of validated genetic loci are strongly associated with higher baseline HbF levels in SCD. For induced HbF levels, genetic approaches using candidate single nucleotide polymorphisms (SNP) have identified some of these same loci as also associated with induction. However, SNP associations to induced HbF are only partially independent of baseline levels. Additional approaches to understanding the impact of hydroxyurea on HbF and its other therapeutic effects on SCD include pharmaco-kinetic, gene expression and epigenetic analyses in patients and through existing murine models for SCD. Understanding the genetic and other factors underlying the variability in therapeutic effects of hydroxyurea for pediatric SCD is critical for prospectively predicting good responders and for designing other effective therapies.