Novel Immunomodulatory Drugs (IMiDs®): A Potential, New Therapy for β-Hemoglobinopathies.

Sickle cell anemia (SCA) and β-thalassemia constitute a public health problem worldwide and new therapies are needed ¹. Inhibition of hemoglobin S (HbS) polymerization is a major target for therapeutic approaches in SCA. New experimental therapies including hydroxyurea (HU) have attempted to augment the synthesis of fetal hemoglobin (HbF) and improve upon current treatment ². We examined whether immunomodulatory analogs of thalidomide (IMiDs®) which have effects on hematopoiesis and are currently under evaluation for the treatment of hematological cancers could stimulate erythropoiesis and hemoglobin synthesis ³. Clinical trial results have demonstrated that Thalidomide and Revlimid™ reduce or even eliminate the need for red blood cell transfusions in some anemic myelodysplastic patients ^4,5. We demonstrate here that CC-4047 (Actimid™) and CC-5013 (Revlimid™) are potent inducers of HbF in vitro and synergize with hydroxyurea during erythroid differentiation of CD34 progenitors isolated from human donors. In addition, we show by gene microarray profiling of CD34 differentiated cells that IMiDs® regulate specific erythroid genes that participate in hemoglobin synthesis. These results support that IMiDs®, alone or in combination with current approved therapies, can be a new approach to augment HbF synthesis, and have the potential to provide an innovative therapy for the β-hemoglobinopathies and other anemias.