Future perspectives for the treatment of sickle cell anemia

Abstract

After decades with few treatment options for individuals with sickle cell disease (SCD), we have entered a treatment era of promising new therapeutic agents. These novel approaches target the diverse pathophysiology associated with SCD (e.g., increased blood cell adhesion, activated coagulation system, hyperinfl ammation, endothelial dysfunction). Potential therapies can be classifi ed according to the “level” of the target intervention and related to the pathophysiology of SCD (upstream versus downstream events). In this chapter, “upstream therapies” refer to those that correct the genetic defect (correction of the sickle mutation in the beta globin gene via hematopoietic stem cell transplantation or gene therapy/gene editing), alter the natural hemoglobin switch phenomenon (enhancement of fetal hemoglobin production via gene therapy/gene editing), or prevent hemoglobin polymerization (e.g., drugs that alter the hemoglobin oxygen affi nity or enhance fetal hemoglobin production). “Downstream therapies” are those aimed at quelling the downstream effects of hemolysis and vaso-occlusion (e.g., anti-adhesive, anti- infl ammatory, or vaso-dilatory agents). This chapter discusses new therapies both in pre-clinical and clinical stages of investigation, and emphasizes those with the highest likelihood for impact on the disease and translation into clinical use over the next decade.