Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia

Abstract

This chapter reviews current understanding of the molecular and cellular basis of the pathophysiology of sickle‐cell anemia, with emphasis on the biophysics of the intracellular polymerization of sickle hemogobin. Factors that modify the severity of the disease manifestations, primarily by altering polymerization tendency, are discussed. This framework is used to present an overview of the major rational approaches to the therapy of sickle‐cell anemia based on inhibiting polymerization with agents that affect either the hemoglobin molecule or the sickle erythrocyte. Discussion of agents that may decrease vascular entrapment of sickle erythrocytes is also presented. Detailed review of the most important current approaches to therapy—pharmacologically elevating fetal hemoglobin—focuses primarily on hydroxyurea, the only drug currently FDA approved for treating sickle‐cell anemia. A brief discussion of other approaches, including stem cell transplantation and gene therapy, concludes the chapter.

Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

“…Deoxygenated HbS polymerizes, leading to erythrocyte rigidity, distortion, membrane damage, and hemolysis. 1,2 Consequently, sickle cell patients suffer repeated vaso-occlusive events characterized by ischemia-reperfusion injury and inflammation. 3,4 These chronic vascular insults lead to numerous end-organ complications such as avascular necrosis of bones, retinal infarction, stroke, acute chest syndrome, pulmonary hypertension, and skin ulceration.…”

Identification and characterization of mechanistically distinct inducers of γ-globin transcription

“…Sickle cell disease results from a change at codon 6 of the adult bglobin gene so that a glutamate is replace by a valine (HbA to HbS) and afflicts 1 in 400 Afro-Americans. The altered b-globin protein aggregates to produce an irreversible deformation of red blood cell morphology and a vasoocculsive disease with severe morbidity [1]. b-Thalassemias arise from a wide variety of genetic mutations which Biochemical Pharmacology 66 (2003) 1755-1768 0006-2952/$ -see front matter # 2003 Elsevier Inc. All rights reserved.…”

Increasing hemoglobin oxygen saturation levels in sickle trait donor whole blood prevents hemoglobin S polymerization and allows effective white blood cell reduction by filtration

“…The improved filterability could also have been due to filtration at 4°C rather than at room temperature. Polymer formation in Hb AS RBCs is retarded at 4°C compared to room temperature or body temperature 12 …”