|Front Page Previous Story Next Story||
It's Not the Shape, It's the Substance|
NIDDK's Rodgers Offers Sickle Cell Update
By Rich McManus
Photos by Ernie Branson
On the Front Page...
For many years, doctors thought that the excruciating pain associated with sickle cell disease crisis was due to the sickled shape of the cell the things were contorted like sharp boomerangs rather than like friendly little disks and were thus tearing up the microcirculatory systems of patients.
Continued...But thanks to intramural research by such investigators as Dr. Connie Noguchi and Dr. Alan Schechter at NIDDK, we now know that it is the chemical properties of sickled cells more than their shape that impose the penalties of sickle cell disease. "It is the accumulation of intracellular polymers, not the sickling of cells, that causes pathogenesis," explained NIDDK deputy director Dr. Griffin Rodgers, who spoke at Clinical Center Grand Rounds recently. He holds out the hope of eventual stem cell or gene therapy as a cure for sickle cell disease, and illuminated gathering knowledge of the disorder, including recent studies by Schechter and his colleague Dr. Mark Gladwin of the Clinical Center implicating nitric oxide as a key contributor to the vascular constriction that is a hallmark of the disease.
Not every patient experiences the same level of severity; there are modifying factors owing to genetic and physiologic differences among patients. With respect to the former, scientists have been able to trace the migration of the sickle cell gene from the Old World to the new, more than 4,000 years ago. It appears to have originated in perhaps four sites in antiquity: Senegal (from which the least harmful condition emerged), Benin (home of an intermediate phenotype), India/Saudi Arabia (a mild, almost inconsequential version) and Bantu (associated with the most severe cases).
Rodgers, an expert on hemoglobin, which is a key factor in sickle cell disease, described several decades of NIH studies on fetal hemoglobin and its genetic control mechanisms. He and colleagues found that a cancer drug hydroxyurea can increase levels of fetal hemoglobin, thus moderating the disease's consequences. They launched the NIH Hydroxyurea Trial at the Clinical Center, in which patients remained at the hospital for up to 3-4 months while physicians tried escalating doses of the drug in a search for the optimal amount.
"Most patients took 2 or 3 weeks to respond," Rodgers reported, and while most experienced benefits, about 25-30 percent did not. "Some began to feel better even before their fetal hemoglobin increased, so maybe there were other mechanisms at work."
In the 1990s, NHLBI funded a multicenter trial that was stopped early because, as a May 1995 article in the New England Journal of Medicine reported, hydroxyurea was associated with a 50 percent reduction in the frequency of painful sickle cell crisis, required less frequent blood transfusion, and reduced instances of "chest syndrome," a common cause of death in sickle cell patients.
In 1998, the FDA approved hydroxyurea for use in sickle cell disease; it remains the only drug approved for that ailment.
Last year, the Journal of the American Medical Association published a 9-year followup study of patients taking hydroxyurea. It showed continued increase in fetal hemoglobin levels, less acute chest syndrome occurrence and improved survival. The drug is now being considered for use in children, said Rodgers.
Studies at the CC continue to refine the pathogenesis of hemolysis in sickle cell disease, and chemical factors affecting microvascular (or blood vessel) constriction. NIDDK's Schechter and Gladwin have shown how nitric oxide contributes to complications in the disease by regulating vasodilator tone and inhibiting platelet aggregation and adhesion, among other properties.
Rodgers envisions widening opportunities to intervene with drugs, and sketched the beginnings of an approach to a cure. "Hematopoietic stem cell transplantation is one option we plan to pursue, but only one-quarter of patients have a suitable donor," he said. "The holy grail for us is gene therapy, but unfortunately that path is still a ways off. We need improved methods to recognize true hematopoietic stem cells and to expand their number and ultimately to have the replacement gene function in cells destined to become red cells. At the moment that's a difficult proposition."
Cord blood might be useful as a source of hematopoietic stem cells for eventual gene therapy, he suggested, adding that he is working with Dr. Elizabeth Read and others at the Clinical Center's department of transfusion medicine to study this approach. Rodgers underscored the importance of the CC as a venue for breakthroughs in sickle cell disease: "The Clinical Center has been and continues to be enormously valuable to our studies and those of our colleagues. It is the jewel of the Department of Health and Human Services, and I truly believe that."
Up to Top