Searching for a drug that may treat sickle cell disease (SCD) blood disorder researchers identified a protein responsible for regulating the production of hemoglobin present in erythrocytes (red blood cells). The identified protein is a signaling molecule and a kinase known as HRI. HRI was seen to regulate the iron-carrying component of blood, hemoglobin. The results of this study were recently published in the scientific journal, Science.
Performing lab tests on cultured human cells revealed that inhibiting HRI resulted in a reduction of the characteristic sickling properties of SCD that cause a distortion of the red blood cell shape ultimately giving the disease its name. "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," explains study co-leader Gerd A. Blobel, MD, PhD, a scientist at Children's Hospital of Philadelphia (CHOP).
The results of the research study provided evidence of HRI and its role in a unique process known as "hemoglobin switching”; the biochemical transition normally occurring in infants where red blood cells switch from production of a fetal form of hemoglobin to the adult form. Therefore, it is known that the mutation responsible for SCD is actually present in the adult form of hemoglobin, which explains SCD happens to affect patients only after birth.
SCD mutation leads to red blood cells becoming abnormally crescent-shaped that clog blood vessels and damages organs; which is painful and life-threatening to affected individuals. The current standard treatment for SCD, prescribed by hematologists, is a hydroxyurea drug that increases fetal hemoglobin. Unfortunately, this treatment is not effective for all patients and so researchers are seeking other options.
Utilizing CRISPR gene-editing techniques, researchers screened a class of domains encompassing protein kinases; enzymes that can be inhibited by a small molecule. This screening method allowed the discovery of HRI, the kinase capable of aiding in the silencing of fetal hemoglobin production in red blood cells. Additionally, these results informed researchers how HRI works to suppress fetal hemoglobin production and how, if inhibiting HRI, can fetal hemoglobin rise.
Without altering the viability or maturation of red blood cells, a reduction of “sickling” was achieved on SCD patients, proving that inhibition of HRI function was not a loss. Researchers believe that developing a drug that inhibits HRI might not only be effective for SCD but also as a treatment option for a range of other hemoglobin disorders. "Our long-term goal is to carry out follow-up studies to evaluate whether this approach improves clinical outcomes in patients," said Blobel. "At this point, our results suggest that HRI is a potential target for a new treatment for disorders of hemoglobin."
Source: Children's Hospital of Philadelphia, Science