Awakened gene aids inherited anemias.

One could think of it as the "Sleeping Beauty" therapy for two inherited blood disorders.

Like a biochemical Prince Charming, a common food additive can awaken a sleeping gene that then ameliorates the symptoms of sickle cell anemia and betathalassemia, a new report suggests. Although tested on only a small number of patients so far, the substance may one day offer a lifelong treatment for the two devastating anemias.

The food additive, a flavor enhancer called butyrate, works by switching on the gene responsible for making the fetal form of hemoglobin -- the protein inside red blood cells that ferries inhaled oxygen from the lungs to distant tissues. During embryonic development, organisms as diverse as humans, monkeys, and cows make lots of fetal hemoglobin -- which has an enhanced affinity for oxygen - in order to draw sufficient quantities of the gas from their mothers' bloodstreams through the placenta.

The fetal hemoglobin gene usually slacks off within the first six months of life, and individuals switch over to making the adult form of hemoglobin. However, people with sickle cell anemia and beta-thalassemia have genetic defects in their adult hemoglobin gene. In sickle cell anemia, the faulty gene makes a sticky protein that causes red blood cells to warp and twist into the shape of sickle blades, causing them to lodge painfully in small blood vessels. In beta-thalassemia, the same gene may not function at all, leading to sparse, pale, short-lived red blood cells.

In the 1970s, physicians noticed that some adult Saudi Arabian and Indian patients with sickle cell anemia developed only mild symptoms because they had somehow continued to make high amounts of fetal hemoglobin, which prevented their red blood cells from sickling. In 1985, researchers led by pediatric hematologist Susan P. Perrine of Children's Hospital Oakland (Calif.) Research Institute discovered that the infants of diabetic mothers delayed their switch to adult hemoglobin because of their exposure to elevated concentrations of aminobutyric acid, a chemical compound related to butyrate, in their mothers' blood.

To capitalize on the link between the two findings, Perrine and her colleagues gave three sickle cell anemia patients and three beta-thalassemia patients daily infusions of a butyrate solution for either two or three weeks. In the Jan. 14 NEW ENGLAND JOURNAL OF MEDICINE, they report that the treatment boosted the patients' production of fetal hemoglobin by up to 45 percent, with few side effects.

Moreover, one of the beta-thalassemia patients experienced "complete reversal" of her disease, according to hematologist Douglas V. Failer of Boston University School of Medicine, one of the researchers who conducted the study. "Looking at her blood, you would not know that she had thalassemia' he says. He and his colleagues have just begun clinical tests of an oral form of their butyrate drug.

In a second report in the same journal, Griffin P. Rodgers of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md. and his colleagues report that a combination of the anticancer drug hydroxyurea and the red blood cell growth factor erythropoietin increased the fetal hemoglobin concentrations in four patients with either sickle cell anemia or beta-thalassemia.

Hydroxyurea blocks DNA replication, indirectly causing a buildup of fetal hemoglobin. However, the drug has serious side effects and may cause chromosome damage.

Nevertheless, hematologist H. Franklin Bunn of Brigham and Women's Hospital in Boston expresses guarded optimism about the prospects of butyrate and hydroxyurea. "It seems likely that such agents, either alone or in combination, will eventually lead to safe and effective treatment for two of our best-understood, yet most challenging genetic disorders," he writes in an editorial accompanying the new reports. However, he cautions that physicians must first test the efficacy of the potential therapies in many more patients.