title: Pathophysiologically based drug treatment of sickle cell disease.
abstract: Sickle cell disease is a systemic disorder that is caused by a mutation (Glu6Val) in the gene that encodes beta globin. The sickle hemoglobin molecule (HbS) is a tetramer of two alpha-globin chains and two sickle beta-globin chains, and has the tendency to polymerize when deoxygenated. HbS facilitates abnormal interactions between the sickle erythrocyte and leukocytes and endothelial cells, which trigger a complex pathobiology. This multifaceted pathophysiology provides the opportunity to interrupt the disease at multiple sites, including polymerization of HbS, erythrocyte density and cell-cell interactions. For example, it is possible to induce higher concentrations of fetal hemoglobin, which disrupts the pathology-initiating step of HbS polymerization. Furthermore, it is possible to improve the hydration of sickle erythrocytes and it might be feasible to counteract the endothelial, inflammatory and oxidative abnormalities of sickle cell disease. A therapeutic approach that targets several sites of pathobiology might be most promising.
authors.affiliation: Center of Excellence in Sickle Cell Disease, E248, Boston Medical Center, 88 E. Newton Street, Boston, MA 02118, USA. mhsteinb@bu.edu
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D000893:Anti-Inflammatory Agents; D000986:Antisickling Agents; D001374:Azacitidine; D005319:Fetal Hemoglobin; D006451:Hemoglobin, Sickle; D006918:Hydroxyurea; D011761:Pyrrolidonecarboxylic Acid; D027981:Symporters; D000096922:K Cl- Cotransporters