Study Identifies FDA-approved Medications With Potential for Treating SCD

Using a newly developed assay, researchers identified seven U.S. Food and Drug Administration (FDA)-approved medications that may be effective, with minimal safety issues, in treating sickle cell disease (SCD).

Their findings were reported in the Journal of Clinical Medicine, in the study, “Large-Scale Drug Screen Identifies FDA-Approved Drugs for Repurposing in Sickle-Cell Disease.”

SCD is caused by a mutation in the HBB gene, which carries instructions to make the oxygen-carrying protein hemoglobin. The mutant hemoglobin, commonly referred to as hemoglobin S (HbS), forms clumps, leading to problems with red blood cells.

One strategy for treating SCD is through the re-expression of fetal hemoglobin (HbF). As its name suggests, fetal hemoglobin is a form of hemoglobin that is produced during fetal development. Usually, HbF is replaced by an adult form of hemoglobin in the first few months of life.

However, people with a benign condition called hereditary persistence of fetal hemoglobin (HPFH) continue to express HbF. People with SCD who also have HPFH tend to have milder disease, because HbF can prevent HbS from clumping. As such, inducing HbF expression (in people who don’t have HPFH) could be therapeutic for people with SCD.

In the new study, researchers at the Ohio State University developed a novel cell assay to identify compounds that promote HbF expression. Simplistically, the assay involves using a HbF-specific antibody to detect the protein in cells in dishes.

Using this assay, the researchers then screened the National Institute of Health (NIH) Clinical Collection, a library of 725 small molecules that have been approved by the FDA. The idea was to find already-approved medications that promoted HbF expression.

The benefit of using already-approved medications, as opposed to developing therapies from scratch, is that approved drugs have well-established safety profiles in people. Re-purposing drugs also cuts down on development costs.

Experiments were done in both cell lines and in cells taken from a person with SCD. In both models, there were nine molecules that increased HbF expression by at least 1.5 times. These were: daunorubicin, epirubicin, pyrimethamine, mafenide acetate, prednisolone, quinidine hydrochloride, perphenazine, felodipine, and duvadilan.

Additional experiments in other cell lines indicated that the most efficacious molecules, in terms of promoting HbF expression, were pyrimethamine, imatinib, and quinidine hydrochloride.

Also, with the exception of daunorubicin and epirubicin, the compounds were generally not toxic to cells.

“Daunorubicin and epirubicin are anthracyclines commonly used in chemotherapy and thus their toxicity on these cell lines is expected. It is important to note that since these drugs are administered intravenously and commonly are associated with adverse side effects, it is highly unlikely that these drugs would translate well to SCD patients,” the researchers wrote.

Imatinib also had some toxic effects, but only in cell lines with a specific cancer-associated genetic mutation — though this medication effectively increased HbF levels regardless of the presence of that mutation. Further experiments indicated that imatinib increases HbF levels by causing rearrangements in the physical structure of DNA within the cell.

“We suggest pyrimethamine and imatinib as strong candidates for repurposing due to their strong effects on HbF expression, low cytotoxicity, and safe history of use in humans,” the researchers concluded. “With further testing and in vivo characterization, these drugs have real potential for combating SCD on a global scale.”