Researchers have discovered a small molecule that enhances the production of fetal hemoglobin in human blood stem cells, leading to a reduction in sickled red blood cells in mice. This development demonstrates the potential for creating more effective treatments for sickle cell disease.
Sickle cell disease is a relatively uncommon but the most prevalent inherited blood disorder, impacting over 100,000 individuals in the United States, predominantly among the Black population, according to the Centers for Disease Control and Prevention. While hydroxyurea, a medication, can help ease pain and decrease hospital visits, its effectiveness varies among adults. A team at Boston Medical Center (BMC) has identified an innovative small molecule that may reduce sickling of red blood cells and alleviate symptoms. Their findings were published in Science Advances on July 31, 2024, suggesting a promising pathway for better therapeutics.
“We have found a potentially groundbreaking strategy that could give hope to sickle cell disease patients who do not benefit from standard treatments,” says Shuaiying Cui, PhD, the senior author of the study and a researcher at BMC’s Center of Excellence in Sickle Cell Disease.
In sickle cell disease, the red blood cells take on a “sickle” or crescent shape due to a genetic mutation that impacts hemoglobin, the protein responsible for transporting oxygen from the lungs to body tissues. This mutation causes hemoglobin molecules to cluster together, obstructing blood flow and causing intense pain for patients. However, fetal hemoglobin, which typically diminishes after birth, can help reduce the number of sickled red blood cells. Hydroxyurea functions by increasing fetal hemoglobin levels but can sometimes cause toxicity and isn’t effective for everyone.
The research team tested the impact of a small molecule that targets the peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1 α), a protein found in fatty tissue that contributes to the growth and survival of red blood cells, on the production of fetal hemoglobin and the presence of sickle cells.
The findings revealed that the molecule, SR-18292, boosts fetal hemoglobin production in human blood stem cells and significantly reduces the prevalence of misshapen red blood cells in mice with sickle cell disease. This indicates that SR-18292 may improve the condition independently. Moreover, when combined with hydroxyurea, SR-18292 further increased fetal hemoglobin production. “Our study shows that using a small molecule with hydroxyurea enhances fetal hemoglobin production through different pathways. This could provide an essential new treatment option for sickle cell disease patients who do not respond adequately to hydroxyurea alone,” said Cui, who is also an associate professor of hematology and medical oncology at Boston University Chobanian & Avedisian School of Medicine.
To investigate whether SR-18292 influences the genes responsible for fetal hemoglobin production, the researchers conducted single-cell RNA sequencing on human blood stem cells treated with the molecule. They found various genes with altered expression levels after treatment, including the downregulation of BCL11A, a gene that typically inhibits fetal hemoglobin production, and which is the target of the first CRISPR gene editing treatment for sickle cell disease.
Recently FDA-approved therapies for sickle cell disease, which are available at BMC, are expensive and cannot yet be scaled for global use due to the complex nature of these treatments. Cui expresses hope that this research marks the initial step towards creating a therapy accessible to patients in underserved communities.
“This achievement signifies a major advancement in our quest at BMC for more effective treatments for all sickle cell disease patients. We aspire to develop a drug that can reach patients worldwide who currently lack access to existing gene therapies,” states Cui.
