Researchers study a new way to treat sickle cell disease

Activating a protein in red blood cells may improve anemia and alleviate acute episodes of severe pain for people living with sickle cell disease   

Swee Lay Thein, M.B., D.Sc., a senior investigator and chief of NHLBI’s Sickle Cell Branch, shares insight into a decade-long research journey that may lead to new ways to help people living with sickle cell disease.    

Q: What is sickle cell disease?    

Sickle cell disease (SCD) is an inherited blood condition that occurs when the body produces an abnormal hemoglobin. Hemoglobin is a protein in red blood cells that helps deliver oxygen to different tissues in organs throughout the body. However, in SCD, the abnormal hemoglobin (HbS) forms fibers under low oxygen conditions, changing red blood cells from normal donut-shaped discs to abnormal shapes, including crescent-shaped moons. These changes are referred to as “sickling.” When red blood cells sickle, they can clump together with other cells in the blood and block blood flow, which can lead to complications – especially severe pain.   

Q: Why is it important to study new ways to treat pain in SCD?  

A: For people living with SCD, acute pain is so severe that it is called a “crisis.” Sickled red blood cells are also highly fragile and have a short life span. Therefore, people living with SCD experience anemia throughout their life. To prevent pain crises and alleviate anemia in people living with SCD, researchers, including those in our group, have been studying new ways to prevent blood cells from sickling. We believe that reducing sickling should also improve anemia as red blood cells will be less likely to breakdown.

Q: What are you and researchers studying as a new treatment option for SCD pain?  

A: When we looked at genes involved with SCD, we found that children and adults hospitalized for sickle pain were more likely to have variations of the gene PKLR. This gene expresses production of the enzyme pyruvate kinase (PKR) in red blood cells, which is a kind of protein that supports cellular health and metabolism. This discovery led to us study how treatments that stimulate PKR activity may prevent or alleviate severe pain crises. This is important, because generally when people have a PKR deficiency, as caused by inherited mutations in the PKLR gene, referred to as pyruvate kinase deficiency, their red blood cells are very fragile and they have severe anemia. This drug was originally developed for treating patients with inherited pyruvate kinase deficiency and recently approved by the Food and Drug Administration in February 2022. If activating PKR can improve red blood cell health, it will make sickle cell disease milder and provide a new treatment strategy for patients.

Interestingly, this research started after it was reported that sickle cell carriers who have no clinical symptoms can still have SCD (like those with two copies of the sickle gene). The reason, we’re finding, is due to adaptive PKLR mutations.  

Q: What are the next steps for clinical research?   

When we conducted an early phase 1 clinical research trial, we found that activating PKR in patients with SCD through an oral therapy was safe and well tolerated. We’ll continue to assess the long-term safety and efficacy of this approach with more research. We’ll specifically look at how this oral therapy may reduce the number of sickling events people experience and also see if it can improve anemia.    

Q: What is unique about this treatment approach?    

This treatment approach is still in the early research phases, but it has the potential to break new ground. Other anti-sickling therapies have targeted the problem in conventional ways by looking at how to increase the size of red blood cells, how to improve cell hydration, how to improve hemoglobin binding of oxygen, and how to increase fetal hemoglobin. The goal of these therapies has been to help cells deliver oxygen to tissues throughout the body. But we started our research by studying characteristics of the patients themselves. Then, we assessed how repurposing a drug developed for treating PKR deficiency may help people with SCD.  

Researchers also saw that the initial promising outcome had similar effects in healthy volunteers – people without mutated PKLR genes. They found that activating PKR increases ATP, an energy molecule, which is useful for other conditions. This is a good example of “bed-to-bench-to-bed” research.    

Q: How may these insights into PKLR’s anti-sickling properties inform other areas of research?    

A: There could be multiple ways to mitigate sickling. For example, other molecules involved in cellular health and energy production could activate PKR and produce similar anti-sickling properties.    

We also envision that people could take PKR activators with other SCD pain therapies, such as hydroxyurea. These therapies may also provide options for people with SCD who cannot tolerate hydroxyurea, a standard therapy for SCD that has been used for more than 30 years.     

Q: What treatment options are currently available for people with SCD who experience a pain crisis?    

Current treatment options - hydroxyurea, crizanlizumab, and voxelotor – aim to reduce the frequency of painful crises but they do not alleviate the pain, which requires strong painkillers. For example, hydroxyurea supports hemoglobin production and has been shown to reduce about half of the number of painful events a person with SCD may experience.

Voxelotor also supports hemoglobin production, and some studies have shown it can boost hemoglobin levels by 40%.  

Crizanlizumab takes a different approach in supporting circulation. Instead of focusing on improving hemoglobin in red blood cells, this therapy aims to make blood vessel walls less sticky, which helps prevent sickled cells from clotting together and altering blood flow.    

Since these therapies have different side effects, it’s important for people living with SCD to work with their healthcare provider to identify a treatment approach that works best for them.    

Q: What other SCD topics are you and researchers at NHLBI studying?    

A: We continue to work with William A. Eaton, M.D., Ph.D., an investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, to study “anti-sickling” properties of cells. We are assessing how this information may help create new therapies and drugs to help people living with SCD and other types of inherited blood conditions. We are also working with Bruce J. Tromberg, Ph.D., and his team at the National Institute of Biomedical Imaging and Bioengineering to explore optical techniques of monitoring effects of new SCD treatments on  vascular health, which will help us assess the effectiveness of these treatments for patients with SCD.

Additionally, we’re conducting preclinical research to better understand what can go wrong in people with SCD. As researchers, we’re objective throughout the scientific process. However, we’re always looking for new and improved ways to help people living with this disease.    

Q: Where can people go to learn more?  

We recently published research about PKR expression and SCD in Blood, Blood Advances, and Blood, Cells, Molecules, and Diseases.    

To learn more about sickle cell disease, visit https://www.nhlbi.nih.gov/health-topics/education-and-awareness/sickle-cell.    

To learn more about the Laboratory of Sickle Cell Genetics and Pathophysiology, visit https://www.nhlbi.nih.gov/science/sickle-cell-genetics-and-pathophysiology.