HRI Protein Identified as Possible New Therapeutic Target for SCD, Study Shows

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by Diogo Pinto |

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HRI protein in SCD

The HRI signaling protein was identified as a key negative regulator of hemoglobin production in red blood cells, unraveling a potential new therapeutic target for sickle cell disease (SCD).

Using the gene editing tool CRISPR-Cas9, HRI was found to block the production of fetal hemoglobin, which carries iron required for healthy red blood cells.

Additional tests demonstrated that eliminating the HRI function resulted in increased fetal hemoglobin production and reduced sickling of the red blood cells.

The study, “Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells,” was published in the journal Science.

“We have found a protein with activity specifically in red blood cells that could be a ‘druggable’ target, possibly with a small molecule — a pill that patients could take to treat sickle cell disease,” Gerd Blobel, an MD and PhD, and co-leader of the study, said in a press release.

Scientists were already aware of HRI as a regulator of the production of hemoglobin, the iron- and oxygen-carrying protein of red blood cells.

Now, a research team from the Children’s Hospital of Philadelphia (CHOP), Perelman School of Medicine at the University of Pennsylvania, and Pennsylvania State University revealed more about its function, specifically that this protein is involved in a process called “hemoglobin switching.”

In this transition process, red blood cells switch from producing fetal hemoglobin to an adult form of it. The genetic mutation that causes sickle cell disease is present only in adult hemoglobin, which explains why the disease is diagnosed after birth.

To improve the current standard treatment for SCD, called hydroxyurea, the research team screened for new therapeutic targets. The screening was conducted using the CRISPR-Cas9 technology in a specific type of protein, the protein kinases, that can potentially be inhibited by small molecules.

Researchers not only confirmed that HRI (heme-regulated kinase) inhibits the production of fetal hemoglobin, but also found that a process called hemoglobin switching was affected.

When researchers inhibited the action of HRI, they observed an increase in the levels of fetal hemoglobin in red blood cells.

The increased levels of fetal hemoglobin results in a decreased sickling in red blood cells obtained from SCD patients without hampering the quality of the cells, suggesting that losing HRI function is well tolerated.

Additional studies confirmed the effectiveness of a combination therapy, using an HRI inhibitor and a stimulator of fetal hemoglobin production.

Researchers combined the silencing of the HRI function with an experimental molecule known to increase fetal hemoglobin, pomalidomide. This combination approach had a stronger effect than using each strategy on its own.

The encouraging findings of this study can not only be applied to SCD, but also to other sickle cell disorders, like beta-thalassemia, researchers wrote.

“Our long-term goal is to carry out follow-up studies to evaluate whether this approach improves clinical outcomes in patients,” Blobel said. “At this point, our results suggest that HRI is a potential target for a new treatment for disorders of hemoglobin.”