New molecule may help adults who do not respond to traditional sickle cell disease therapy
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Researchers at Boston Medical Center identified a new small molecule that could benefit people with sickle cell disease who do not respond to hydroxyurea.
Shuaiying Cui, PhD, associate professor of medicine in hematology-medical oncology at Boston University Chobanian & Avedisian School of Medicine and researcher at Boston Medical Center’s Center of Excellence in Sickle Cell Disease, and colleagues evaluated whether the small molecule — SR-18292 — could increase fetal hemoglobin (HbF) production in human blood stem cells and reduce sickled red blood cells in mouse models of the disease.
In one part of the analysis, researchers isolated cells from the peripheral blood of healthy adults and treated them with SR-18292. Following 11 days of treatment, cells demonstrated significant increases in mRNA levels of proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Lower doses (1 or 2.5 M) yielded four- to fivefold increases in PGC-1 alpha, and higher doses (5 to 7.5 M) yielded 10-fold increases.
Fetal gamma-globin mRNA levels increased 2.5-fold at lower doses and four-to sixfold at higher doses.
In mice, 4 consecutive weeks of treatment with SR-18292 induced the synthesis of fetal-gamma globin, more HbF-positive cells and mature red blood cells. It also reduced reticulocytes and sickle cells in the blood.
“Even modestly elevated levels of HbF in adults with sickle cell disease decreases the frequency and duration of acute pain episodes, whereas even higher HbF levels reduce organ morbidity and prolong life,” Cui told Healio.
Healio spoke with Cui about the findings and their implications, as well as the next steps in his group’s research.
Healio: What challenges are associated with treating adults with sickle cell disease who do not respond to hydroxyurea?
Cui: Sickle cell disease causes progressive multiorgan damage, chronic morbidity, pain, disability and early mortality.
Hydroxyurea is the standard of care for adults, and its beneficial effects are due primarily to its ability to increase HbF. However, the response among patients is variable, and patients who respond well can still have life-threatening complications.
Patients who don’t respond have longer and more frequent acute pain episodes, and those with severe forms of sickle cell disease need more emergency room visits or blood transfusions. Transfusions can result in iron overload with widespread organ damage, notably cardiac failure even with iron chelation treatment.
Healio: How did your team discover this small molecule?
Cui: We previously identified PGC-1 alpha as a new protein involved in the regulation of the fetal gamma-globin genes. Unlike targeting many other HbF repressors, upregulation of PGC-1 alpha does not affect red blood cell differentiation, suggesting that modulating PGC-1 alpha activity would be a novel and safer therapeutic approach for treatment. To develop a new gamma-globin inducer based on PGC-1 alpha activation, we used a human-derived red blood cell progenitor line for quick testing of the small molecule compounds that may serve as a PGC-1 alpha agonist for gamma-globin induction. Our initial screening showed that SR-18292 effectively stimulated PGC-1 alpha expression and led to increased fetal gamma-globin expression.
Healio: How have you investigated this molecule so far?
Cui: We further validated the inductive effects of SR-18292 in human primary red blood cell progenitors and examined the in vivo effects of SR-18292 on animal models. SR-18292 administration led to induced HbF synthesis, more HbF-positive cells and mature red blood cells, as well as fewer reticulocytes and sickle cells in the blood of mice with sickle cell disease. Notably, the combination of SR18292 with hydroxyurea also led to more red blood cells with HbF in culture. This enhanced effect of SR-18292 with hydroxyurea suggests that activation of PGC-1 alpha by these compounds might provide a new path for modulating HbF levels with potential therapeutic benefit for patients with less-than-optimal responses to hydroxyurea.
Healio: What are the potential implications if this approach is validated?
Cui: Even modestly elevated levels of HbF among adults with sickle cell disease reduces the frequency and duration of acute pain episodes, while even higher HbF levels reduce organ morbidity and prolong life. PGC-1 alpha comprises a new molecular target beyond previously identified HbF repressors, and activation of PGC-1 alpha provides a new path into hemoglobin regulation for possible therapeutic intervention.
Healio: Is there anything else you’d like to mention?
Cui: There has been good progress with gene therapy, but these treatments are unlikely to become widely applicable due to the need for myeloablative conditioning, prolonged and intense follow-up, and off-target potential. Therefore, orally available small molecule pharmacotherapeutics that up-regulate HbF will offer a widely available treatment. Our next step in this research will be to examine different drug delivery methods, especially oral administration.
Reference:
For more information:
Shuaiying Cui, PhD, can be reached at shuaiyin@bu.edu.
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