Hospital of Philadelphia
Gerd A. Blobel, MD, PhD Photo from Children’s
A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.
The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).
Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.
Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.
“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.
To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.
The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.
Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.
To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.
Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.
The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.
When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”
Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.
The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.
To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.
He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.
HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.