The single-gene disorder, sickle cell anemia affects hundreds of thousands of children in Africa, India, the Middle East and the Mediterranean region. Occurence is also high amongst immigrant populations in America and northern Europe. While molecular biologists have recently shown that the anemia can be partially corrected by switching on fetal hemoglobin, Robert Hebbel argues a case for therapy based on drugs designed to counter the pathophysiology of the disease, rather than the genetics. The sickle RBC membrane has many abnormalities, including excessive amounts of hemichromes. These denatured ferric hemoglobins may facilitate the excessive autooxidation observed in sickle RBC, which generates superoxide and hydroxy free radicals. These highly reactive species may then be responsible for a cascade of interrelated events characterized by dysfunction of the cytoskeleton, lipid bilayer and mechanisms for cation homeostasis. Should such speculation prove valid, it would be rational to aim therapy at the prevention of hemichrome formation or superoxide generation. As in all complex diseases, development of safe and effective therapeutics is dependent on understanding of true pathophysiology.
Bibliographical noteFunding Information:
AdmowledMment The author's laboratory is supported by the National Institutes of Health (HL26139, HL30160, and a Research Career Development Award).