In an important advance in genetic engineering, scientists here have activated a dormant blood-making gene to treat victims of two serious blood diseases, sickle cell anemia and thalassemia.
Doctors at the National Institutes of Health in Bethesda and Johns Hopkins University in Baltimore have at least temporarily improved the blood-making capacity of at least six patients by giving them a drug called 5-azacytidine. The effort still is early and experimental, they warn, and doctors in general should not yet start using this powerful drug.
But an editorial in the New England Journal of Medicine this week called the treatment "a major new step" and "the first encouraging attempt" to manipulate patients' genes by manipulating their DNA, the molecules that make up the genes.
The achievement, the editorial said, demonstrates "beyond doubt" that molecular genetics -- the understanding of gene structure -- "has come to the bedside," with possible application to many diseases.
Both sickle cell anemia and thalassemia are disorders of the way the body makes hemoglobin, the basic red matter in red blood cells. Both diseases can cause disabling anemia, and in sickle cell disease there are sometimes grave "crises" in which the red cells become curved or "sickled".
Sickle cell anemia affects blacks, for the most part, mostly in West Africa, the United States and other nations with populations of African origin. Thalassemia affects Mediterranean peoples, especially Greeks and Italians, but also affects Chinese, Southeast Asians, Arabs and Africans.
Drs. Joseph DeSimone and Paul Heller of the University of Illinois first showed in baboons that 5-azacytidine could make hemoglobin genes "express themselves" or become activated.
This year, a NIH team under Drs. Timothy Ley and Arthur Nienhuis of the National Heart, Lung and Blood Institute began patient trials in collaboration with the Illinois group. They have treated three thalassemia and two sickle cell patients at the NIH Clinical Center, the research hospital on the NIH campus in Bethesda.
In every case, Ley said yesterday, just one week's use of the drug improved the patients' red blood cells to some degree, and the thalassemia patients' anemia was clearly improved.
A report by Ley and colleagues in the New England Journal describes one man, 42, with thalassemia who needed red blood cell transfusions every two weeks. After doctors gave him 5-azacytidine for seven days, he began producing more "good" hemoglobin and did not need a transfusion for 42 days.
In the sickle cell patients, Dr. Nienhuis said, the drug "significantly reduced the tendency of sickled cells to form."
In all cases so far, however, the aim has not been to give patients true treatment, but merely to establish the drug's efficacy and determine a safe, effective way to give it.
What the drug does, Charache explained, is "switch on" a gene that makes a form of hemoglobin -- gamma hemoglobin -- in the womb before birth. At birth this gene is switched off. Switching it back on may now, it seems, begin to substitute normal gamma hemoglobin for some of the more harmful hemoglobin in these blood disorders.
Real trials of the drug for effective sickle cell and thalassemia treatment are at least a year away, Ley said. The "most exciting thing," said Charache, "is that a drug can be effective," and "there is now the possibility of developing better drugs."