The presence of fetal hemoglobin (HbF,α2γ2) is known to reduce the clinical complications of sickle cell disease (SCD). Pharmacologic agents able to induce HbF have been sought after for decades. Agnostic drug screens have been unsuccessful, and progress in identifying novel HbF-inducing agents was slowed by our limited understanding of γ-globin regulation. Our understanding of γ-globin induction was increased significantly by an unbiased genome-wide association study (GWAS) approach, which identified variants in the transcription factor B-cell lymphoma/leukemia 11A (BCL11A) and regulatory elements within the intergenic region HBS1L-MYB as associated with HbF levels. Functional studies subsequently established the roles of BCL11A, MYB, and KLF1 in γ-globin repression, and disruption of the BCL11A erythroid enhancer element is now a gene therapy target in >1 clinical trial. Gene therapy may provide a cure for SCD, either through HbF induction or correction of the causative mutation, but several technical and safety hurdles must be overcome before this therapy can be offered widely, particularly in low-resource countries, where 99% of individuals with SCD reside. Pharmacologic therapies to treat SCD are still needed, and hydroxyurea, developed for use in SCD almost 3 decades ago, remains the only widely used pharmacologic HbF inducer.
Hemoglobin is composed of 2 α-like globin chains and 2 β-like globin chains, with a heme moiety in the middle. In humans, the β-globin gene locus is comprised of 5 different genes (HBE1, HBG1, HBG2, HBD, and HBB), all located on chromosome 11. The α-globin gene locus, located on chromosome 16, is composed of 3 genes (HBZ, HBA1, and HBA2). Early in fetal development, expression of embryonic globin gene (HBE1) declines and is replaced by expression of HbF (HBG1, HBG2). HbF has a higher oxygen affinity than the maternal hemoglobin A (HbA). After birth, in normal individuals, HbF is no longer needed and begins to be replaced by HbA, or adult hemoglobin (α2β2).1 HbF typically makes up <5% of the total hemoglobin at 6 months of age and becomes undetectable by 2 years of age.2 Although all vertebrates studied have a switch from primitive to definitive erythropoiesis, only old world primates, humans, and some ruminants make HbF; this limits the availability of animal models in which to study hemoglobin switching and screen compounds to alter or reverse the switch from HbF to HbA.
Importance of HbF in Sickle Cell Anemia Pathophysiology
Sickle cell anemia (SCA) is caused by the autosomal recessive inheritance of a single base substitution (A-T) in the first exon of the β-globin gene (HBB). This substitution results in the replacement of a negatively charged, hydrophilic amino acid, glutamic acid, by a hydrophobic amino acid, valine, at position 6 [HBB; glu(E)6val(A); GAG-GTG; ...