Identification of new potential therapeutic approach to blood disorders

Scientists detailed a novel way to restart production of fetal hemoglobin (HbF), suggesting a new potential therapeutic approach for some blood disorders. Thalassemias and sickle cell disease are inherited blood disorders that affect hemoglobin, a protein that carries oxygen through the body. Around birth, production of HbF is turned off and shifts to production of “adult” hemoglobin (HbA). In this research, investigators studied hemoglobin genes and their regulation and identified how HbF is turned on in response to high-altitude conditions of low oxygen (hypoxia), an example of a condition in which more red blood cells are needed rapidly. This research identifies a new therapeutic approach to blood disorders of hemoglobin.

The scientists found that a protein called hypoxia-inducible factor 1α (HIF1α) can turn on production of HbF in an adult human blood cell line. Using cutting-edge molecular and genetic strategies, they found that HIF1α binds specific sequences of DNA in regions known to regulate hemoglobin genes and recruits additional proteins to stimulate production of HbF. They uncovered molecular changes in HIF1α, as well as changes in how it interacts with other proteins, that occur in the developmental switch from production of HbF to HbA. They hypothesized that reversing these changes might re-induce HbF production. To test whether this approach could be a potential therapeutic strategy, the scientists treated cells with a drug known to boost red blood cell levels. They found that treating healthy adult donor cells or cells from donors with sickle cell disease with this drug increased production of HbF to levels similar to those induced by treatment with hydroxyurea, which is used to treat sickle cell disease. Treatment of the cells from a donor with sickle cell with the drug also reduced the sickling characteristic of the disease.

The exciting finding that stabilization of HIF1α can induce production of HbF in human blood cells provides important new knowledge in understanding the regulation of hemoglobin production and indicates a potential therapeutic strategy to restart HbF production in people affected by blood disorders. Additional research will be needed to test whether this strategy can be translated from the bench to the clinic..