Small molecule shows promise in lab models for treating sickle cell
Novel molecule SR-18292 found to reduce disease severity in SCD mice
A novel small molecule called SR-18292, which acts to boost the production of fetal hemoglobin, was shown to reduce disease severity in a mouse model of sickle cell disease (SCD) and demonstrated benefits in other lab testing in a new study.
“We’ve uncovered a promising approach that can offer hope to patients with sickle cell disease who have not responded to traditional treatments,” Shuaiying Cui, PhD, a researcher at the Boston Medical Center (BMC) Center of Excellence in Sickle Cell Disease and the study’s senior author, said in a BMC press release.
Experiments in human blood cells showed the anti-sickling effects of SR-18292 combined with hydroxyurea, an established SCD treatment thought to also act on fetal hemoglobin, were more potent when compared with those of either therapy alone.
“Our research shows that combining a small molecule with hydroxyurea enhances the production of fetal hemoglobin through different mechanisms. This could provide a vital new treatment option for sickle cell disease patients who don’t respond well to hydroxyurea alone,” Cui said.
The study, “PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease,” was published in the journal Science Advances.
Small molecule SR-18292 increased fetal hemoglobin in human blood cells
Sickle cell disease is caused by mutations that lead to the production of an abnormal form of hemoglobin — the protein that red blood cells use to carry oxygen throughout the body. The abnormal hemoglobin tends to clump up inside red blood cells, deforming them into the sickle-like shape that gives the disease its name and ultimately drives its symptoms.
SCD specifically affects the adult version of hemoglobin. Fetal hemoglobin, or HbF for short, is an alternative version of this protein that’s made during early fetal development. Normally, the body stops making HbF and switches on the production of the adult version of hemoglobin shortly after birth.
In people with sickle cell, boosting HbF levels has been shown as a viable strategy for reducing red blood cell sickling and ultimately combatting the disease. However, treatment options targeting HbF are limited.
Previous research has shown that activating PGC-1 alpha, a protein that helps regulate the activity of various genes within cells, can increase HbF production in blood cells. Spurred on by that discovery, researchers at BMC tested the effects of SR-18292, a small molecule that activates PGC-1 alpha, in cell and animal models of SCD.
Initial experiments in human blood stem cells confirmed that SR-18292 treatment was able to increase HbF levels as expected.
Importantly, the researchers noted that the effect of SR-18292 combined with hydroxyurea was more potent at boosting HbF production than either therapy on its own.
Genetic analyses conducted in human blood stem cells also indicated that SR-18292 increased the activity of several genes that are known to boost HbF production. At the same time, the researchers also found that SR-18292 decreased the activity of genes that normally act to turn off HbF production, including BCL11A, which is the gene targeted by Casgevy (exagamglogene autotemcel) — a CRISPR/Cas9-based gene-editing therapy approved late last year for SCD.
Scientists call SR-18292 a ‘promising’ potential SCD treatment
Following the cell experiments, the researchers tested the effects of this small molecule in a mouse model of SCD. In line with the cell experiments, results in mice showed that SR-18292 was able to boost HbF production.
SR-18292-treated mice also showed fewer signs of premature red blood cell destruction and organ damage compared with their untreated counterparts. The researchers also found evidence suggesting that SR-18292 increased the lifespan of red blood cells in SCD mice and reduced the number of sickled cells in treated animals.
“Induction of HbF by SR-18292 with improved [blood cell health] and reduced organ damage in SCD mice suggests that this small-molecule activator of PGC-1 [alpha] might be a new class of drugs that alone or in combination with other agents can enhance clinically useful increments of HbF,” the researchers wrote.
This breakthrough represents a significant step forward in BMC’s quest for more effective therapies to treat sickle cell disease for all patients.
The team noted that, in addition to suggesting that SR-18292 may be an effective sickle cell treatment, the results more broadly show “proof of principle for targeting PGC-1 [alpha] and its modulators to develop more effective HbF-boosting agents for SCD.”
Overall, the scientists concluded that “SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.”
Cui said that the team hopes this treatment strategy may one day be used to help sickle cell patients worldwide manage their disease, especially those who don’t have access to cutting-edge, expensive treatments like gene therapies.
“This breakthrough represents a significant step forward in BMC’s quest for more effective therapies to treat sickle cell disease for all patients,” Cui said.
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