From the Journals

Researchers identify potential sickle cell disease target



Researchers have identified a repressor of fetal hemoglobin (HbF), which they assert could offer a therapeutic target for patients with sickle cell disease (SCD) and some forms of beta thalassemia, according to a new paper published in Science.

Strategies to boost HbF have so far been limited to gene therapy and hydroxyurea, which has been shown to have limited efficacy.

The finding was made using a tailored CRISPR screen of adult human erythroid cells; the CRISPR screen targeted protein kinases, which are controllable by small molecules, which makes them more feasible for treatment therapeutically, researchers wrote.

“Using an improved CRISPR-Cas9 domain-focused screening approach, we identified the erythroid-specific kinase HRI [heme-regulated inhibitor] as a potentially druggable target that is involved in HbF silencing,” wrote Gerd A. Blobel, MD, PhD, of Children’s Hospital of Philadelphia and his colleagues.

HRI is an erythroid-specific kinase that controls protein translation. Once identified, depleting HRI resulted in an increase of HbF production and reduced sickling in cultured erythroid cells. Researchers said that diminished expression of the transcription factor BCL11A, an HbF repressor, accounted for the effects of HRI depletion.

The results with erythroid cell cultures suggest that HRI loss is well tolerated, but the mechanism of inducing fetal hemoglobin is still not fully understood, the researchers noted. Also, while HRI may be targetable, the extent of the benefits of this targeting are not yet known.

“It remains to be seen whether HRI inhibition in SCD patients would elevate HbF levels sufficiently to improve outcomes,” the researchers wrote. “HRI inhibition elevated HbF levels to a point at which it reduced cell sickling in culture, suggesting that pharmacologic HRI inhibitors may provide clinical benefit in SCD patients. Moreover, in light of our results, combining HRI inhibition with an additional pharmacologic HbF inducer may improve the therapeutic index. "Funding was provided by NIH training grants and Cold Spring Harbor Laboratory. Three of the authors reported that they are inventors on a patent submitted by the Children’s Hospital of Philadelphia that covers the therapeutic targeting of HRI for hemoglobinopathies.

SOURCE: Grevet J et al. Science. 2018 Jul 20. doi: 10.1126/science.aao0932.

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