The first animal model for sickle cell anemia was announcedthis week at the annual meeting of the National Sickle CellDisease Program in Philadelphia.
Developed by biologists at the Department of Energy's OakRidge National Laboratory in Tennessee, the geneticallyengineered mice carry defective hemoglobin that can cause redblood cells to warp and clog capillaries.
"It's a significant achievement," said hemoglobin researcherMarty Emanuele, vice president of preclinical research anddevelopment at CytRx Corp. of Norcross, Ga. "There was nopreclinical model of the disease."
CytRx has licensed a potential treatment, RheothRx, toBurroughs Wellcome Co., which has taken this copolymer intoPhase II trials designed to treat problems with vascular bloodflow by coating blood cells so they can slip around blood clots.
Without animal models, researchers have used ex vivopreclinical tests in human cells, he said, which provide lesstoxicity data than work in whole animals.
A second potential treatment would boost levels of fetalhemoglobin in patients' red blood cells. Researchers havestarted clinical trials of two fetal hemoglobin approaches. Oneapproach uses the chemotherapy drug hydroxyurea, which istoxic, in combination with the hormone erythropoietin, whichstimulates red blood cell maturation. While the mechanism ofaction is not clear, the combination has increased production offetal hemoglobin, which has a higher affinity for oxygen thanadult hemoglobin (a feature that allows fetuses to draw oxygenfrom their mothers' bloodstream).
The other method of stimulating fetal hemoglobin productionrelies on administering the fatty acid butyrate.
Other than these experimental treatments, "patients reallydon't have much," Emanuele said.
"There is a need for better drugs for long-term therapy,"agreed Dawn Bobbitt, a counselor at the Sickle Cell DiseaseResearch Foundation in Los Angeles.
As the hemoglobin in red blood cells gives up oxygen duringcirculation, the process causes the cells to sickle. If the red cellslose too much oxygen before recharging in the lungs, the sickle-cell hemoglobin begins to gel and the cells warp, sometimesinto a shape resembling a sickle, and lose their ability tosqueeze through capillaries.
This process cuts off oxygen, causing more cells to sickle andclump, leading to a crisis that causes painful cramps from abuildup of lactic acid in the muscles. Skin ulcers and kidneycomplications can ensue.
Patients are hospitalized during these crises, Bobbitt said,where they take pain medication to alleviate symptoms. Theonly preventive measures are ample fluid intake, goodnutrition and a limit to strenuous activity.
Oak Ridge National Laboratory senior staff biologist RaymondPopp created the mouse model by altering one strain'shemoglobin with ethylnitrosourea so it retains oxygen morelike human hemoglobin. These genetically altered mice werecross-bred with a transgenic strain containing a rare humansickling hemoglobin from the Antilles region of the Caribbean.
Through controlled breeding, Popp said he has developed a lineof mice that exhibit symptoms of a human who has sickle celldisease.
"This should, pretty quickly, lead to attempts at preventivedrug therapy in sickle-cell mice," he said, "and eventually leadto human trials."
Sickle cell anemia was one of the first inherited diseases to bedefined on a molecular level. It afflicts up to 100,000Americans of African descent. The disease may have had anevolutionary advantage because it apparently helps carrierssurvive malaria, which is transmitted to the blood bymosquitoes in equatorial regions.
The biotechnical work by Popp and colleagues exemplifiesresearch that could take place in a proposed Center forBiological Sciences at the U.S. Department of Energy laboratorymanaged by Martin Marietta Energy Systems Inc. The workwas funded by the Department of Energy and the NationalInstitutes of Health.
-- Nancy Garcia Associate Editor
(c) 1997 American Health Consultants. All rights reserved.