Protein in Hypoxia Response Can Boost Fetal Hemoglobin, Study Says

Finding may offer therapeutic avenues for sickle cell disease or beta-thalassemia

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Activation of a protein critical for the body’s response to low oxygen leads to increased levels of fetal hemoglobin in adults — a finding that could offer new therapeutic avenues for people with sickle cell disease (SCD) or beta-thalassemia, a study says.

In cell cultures of red blood cells from adult SCD patients, treatment with a proline hydroxylase inhibitor — which activates the hypoxia (or low oxygen) response — led to increases in fetal hemoglobin (HbF). Research has shown that persistent expression of HbF can alleviate symptoms of blood disorders such as sickle cell disease.

“Our findings indicate that proline hydroxylase inhibitors might be useful for treatment of sickle cell disease or beta-thalassemia, where turning on HbF production has therapeutic benefits,” Mitchell J. Weiss, MD, PhD, the study’s corresponding author and chair of hematology at St. Jude Children’s Research Hospital in Memphis, Tennessee, said in a press release.

The study, “Activation of γ-globin expression by hypoxia-inducible factor 1α,” was published in the journal Nature.

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Hemoglobin is the protein that allows red blood cells to carry oxygen throughout the body. Before birth, HbF consists of two alpha-globin and two gamma-globin subunits. After birth, gamma-globin is switched off and replaced with beta-globin to form the adult version of the protein.

SCD is caused by mutations in the HBB gene that contains instructions for making beta-globin. These mutations lead to the production of a faulty version of hemoglobin, which in turn causes red blood cells to become misshapen and rigid. As such, these cells cannot move easily through blood vessels, blocking blood flow and compromising oxygen delivery to body tissues.

Prolonging or enhancing the production of HbF, which lacks the defective beta-globin subunit, is known to be a promising strategy to treat SCD or beta-thalassemia, another blood disorder caused by mutations in the HBB gene.

“We have known for many years that persistent HbF expression after birth can alleviate the symptoms of sickle cell disease and beta-thalassemia,” Weiss said. “And very high HbF levels can cure these diseases, despite the defective beta-globin genes being present. Therefore, many laboratories are focused on understanding the perinatal switch from gamma- to beta-globin gene expression and figuring out new ways to reverse it with drugs or genetic therapies.”

Study finds HIF1 protein can boost fetal hemoglobin production

In the study, Weiss and colleagues found that a protein called hypoxia-inducible factor 1 (HIF1) has the ability to boost HbF production. HIF1 is normally involved in the body’s detection and response to hypoxia. Under low oxygen conditions, HIF1 accumulates in body tissues and activates a large number of genes to help the body adapt.

Treating red blood cells in culture with a proline hydroxylase inhibitor caused HIF1 to accumulate and bind to areas near the gamma-globin gene. Transcriptional activators, which broadly act to stimulate the activity of nearby genes, were then recruited, thereby increasing the activity of the gamma-globin gene, and allowing for more HbF to be produced.

The researchers also found that red blood cell sickling could be prevented by this process.

Proline hydroxylase inhibitors are a class of medications in late-stage clinical development for the treatment of anemia associated with chronic kidney disease. They act by stabilizing HIF proteins, which stimulate the release of a hormone called erythopoietin from the kidneys. This hormone stimulates the production of red blood cells.

“Approximately 20% of adult sickle cell disease patients develop kidney failure with related anemia,” Weiss said. “Proline hydroxylase inhibitors might serve a dual purpose in these individuals, by stimulating the production of both erythropoietin and HbF.”

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Findings from the study also contribute more broadly to the understanding of why fetal hemoglobin production tends to be increased during red blood cell production after hypoxia — a phenomenon known as “stress erythropoiesis.”

“Identification of gamma-globin as a HIF target gene supports the notion that HbF evolved as a protective mechanism against hypoxia,” Weiss said.

“Studies of hemoglobin over more than 50 years have established many general principles in biology and medicine,” he added. “It is exciting and gratifying that investigations into hemoglobin and globin gene expression continue to produce new, clinically relevant discoveries.”