Mechanisms of Regulation of Fetal Hemoglobin Levels: Implications for Treatment of Sickle Cell Disease

Sickle cell disease (SCD) is caused by one of the most common single gene defects in humans and has severe clinical consequences that affect millions of individuals worldwide. It is well established that sufficient levels of fetal hemoglobin (HbF) postnatally can abrogate the pathophysiologic cause of red cell sickling and hence the morbid manifestations of SCD. Major advances in understanding the basis for developmental globin gene regulation and postnatal HbF silencing in recent years have uncovered the detailed molecular mechanisms involved. These discoveries have led to curative gene therapy and identified potential targets for small-molecule therapeutics that could induce similarly high levels of HbF. Successful development of drugs based on knowledge about the molecular mechanisms of HbF silencing would meet a pressing need for treatments that induce sufficient HbF to prevent the morbidity of SCD and that may be accessible in the near future for the majority of affected individuals worldwide.