Advances in Sickle Cell Disease

Advances in Sickle Cell Disease

Research has led to major breakthroughs in the treatment of sickle cell disease, with promising advances still on the horizon.
By Christina Szalinski, PhD

Since the 1956 discovery of the sickle cell disease (SCD) gene mutation, our understanding of the disease has increased dramatically, with advancements in diagnosis, treatment and management. However, though medicines helped with pain and other symptoms, until 2023, the only cure was a bone marrow transplant, which has challenges of donor availability and potential complications.

Then, in December 2023, the U.S. Food and Drug Administration (FDA) approved two gene therapies that serve as potential cures for those with severe SCD. Physiologists are among those conducting research that would bring about more treatments. Furthermore, the impact of SCD research extends beyond the disease—it has the potential to unlock valuable insights related to other conditions, such as HIV and beta thalassemia.

SCD is a painful and debilitating genetic disease that, in the U.S., predominantly affects Black Americans. A sickle cell crisis occurs when the sickle-shaped red blood cells block blood flow in different parts of the body. This can cause intense pain. Triggers for these crises can include stress, sudden change in temperature, infection, dehydration and certain medications.

The pain can feel like having a fracture in your bone “and it’s not healing, and your bone keeps getting fractured, again and again and again,” explains Akshay Sharma, MBBS, bone marrow transplant physician and researcher at St. Jude Children’s Research Hospital. 

SCD is caused by a mutation in the gene that codes for hemoglobin, the protein in red blood cells that carries oxygen throughout the body. Normally, red blood cells are round and flexible, which allows them to easily move through narrow blood vessels. However, in SCD, the abnormal hemoglobin causes the red blood cells to become fragile (causing anemia), stiff, sticky and sickle-shaped when they lack oxygen. These sickle cells can clump together and block blood flow to organs and tissues, causing pain, tissue damage and other complications such as stroke.

In the long term, SCD can cause blood clots, kidney damage, liver disease, vision loss, splenic sequestration (enlarged spleen and severe drop in hemoglobin), stroke, chronic pain and cognitive decline. “The median lifespan is about 40 to 45 years for individuals with sickle cell disease because there’s all these complications that lead to organ damage,” Sharma says.

New SCD Treatments

The two new gene therapies for SCD edit the DNA within a person’s own blood stem cells to promote the production of fetal hemoglobin or another normal hemoglobin, such as hemoglobin HbAT87Q. These hemoglobins are naturally flexible and do not sickle or aggregate, thereby reducing the frequency and severity of pain crises, as well as the complications associated with red blood cell damage and thrombosis.

The gene therapy made by Vertex Pharmaceuticals, called Casgevy (betibeglogene autotemcel), uses CRISPR/Cas9 technology to induce fetal hemoglobin production. The gene therapy from Bluebird Bio, called Lyfgenia (betibeglogene autotemcel), uses a lentiviral vector to promote synthesis of normal hemoglobin HbAT87Q by the erythroid precursor cells (young blood cells). In clinical trials, these treatments significantly reduced the frequency and severity of pain crises and other complications. Long-term studies will reveal if they have sustained success.

While this new technology would be life-changing for many people with SCD, it requires a patient to spend a month or more in the hospital, first to mobilize and collect their stem cells and then to undergo chemotherapy to eliminate their bone marrow before it is replaced with new genetically modified cells. This carries risks, says Sharma, who was involved in the Vertex clinical trials. It also costs $2 to $3 million for one person. Because of the price tag, insurers may limit which patients are eligible for gene therapy coverage. Sharma is hopeful that in the future there will be a vaccine, which would be less invasive and more cost-effective.

Some patients may opt to have a bone marrow transplant, which has been a treatment for children with severe SCD since the 1980s. However, patients still require chemotherapy to reset their bone marrow, and physicians need to replace it with a close match. As with any transplant, there’s a risk that the body will develop graft versus host disease and reject the new bone marrow cells. This doesn’t happen with gene therapy because it uses the body’s own cells. However, a bone marrow transplant costs less than gene therapy. 

More commonly, people with SCD are treated with a drug called hydroxyurea, which stimulates the production of fetal hemoglobin in the patient’s own erythroid cells. Hydroxyurea reduces the frequency of pain crises and thrombus formation and the need for blood transfusion in SCD patients with severe disease. Though clinical trials of hydroxyurea began in 1984, its mechanism of action is still not fully understood. More recent drugs include voxelotor, which prevents red blood cells sickling, and crizanlizumab, which reduces red blood cell adherence and SCD crises. 

There are also new drugs in clinical trials. Based on the findings of the group of Anna Bogdanova, PhD, at the University of Zurich’s Institute of Veterinary Physiology, the University Hospital Zurich carried out a MemSID Phase II clinical trial of memantine for SCD. A follow-up trial was recently finalized at the Pediatric Hematology Unit at the Emek Medical Center in Afula, Israel. 

“The idea was to help people in [developing] countries because it’s a very cheap drug. It’s already available for treatment of Alzheimer’s disease, and we repurposed it into something for sickle cell disease patients,” Bogdanova says.

Memantine blocks N-methyl D-aspartate receptors (NMDAR), which allow calcium ions to enter the cell when activated. Red blood cells affected by SCD have an increase in abundance and activity of NMDAR, though its role in red blood cells is an emerging area of research. NMDARs are most abundant in the brain but are also found in other tissues of the body, including the heart, bones, kidneys and blood cells. Overactivation of NMDARs might be involved in pain signaling.

“We hope that memantine can be used to stabilize the red blood cells and also to somewhat relieve pain, inflammation and organ damage,” Bogdanova says. It’s too early to know its long-term effects, but the first outcomes for the SCD patients treated with memantine for 12 months are promising, she says. And the drug is well-tolerated by adult and adolescent SCD patients. Bogdanova believes that this small molecule can be combined with hydroxyurea for a more comprehensive treatment approach.

Benefits of Exercise

An even simpler and more readily available approach to managing SCD could be exercise. Laurent Messonnier, PhD, exercise physiology professor at Université Savoie Mont Blanc and researcher at the Interuniversity Laboratory of Human Movement Sciences in France, is studying how physical activity can help those with SCD.

“High-intensity exercise can be dangerous for patients with SCD because it can cause a sickle cell crisis,” he says, “but low- to moderate-intensity exercise is safe and performed regularly can be beneficial for patients with SCD.”

Using a stationary bike and a heart rate monitor, Messonnier had patients maintain a target heart rate during moderate-intensity exercise for 30 to 45 minutes three times a week for eight weeks. “That was sufficient to improve physical mobility, muscle function and quality of life for patients with SCD,” he says. It doesn’t sound like much, but he points out that physical activity can be very demanding for those with SCD because they also have anemia. His team is continuing to study the long-term benefits of regular exercise. 

Inequities Persist

Despite being a more prevalent condition, SCD research has historically received significantly less funding than research into other genetic diseases, such as cystic fibrosis—a genetic disease that predominantly affects white people. SCD is three times more prevalent than cystic fibrosis in the U.S. This funding gap and decreased attention has likely hampered progress in developing new treatments and improving patient outcomes.

Additionally, SCD patients have been marginalized in medical care, where their extreme pain can be dismissed. Data suggest that children with SCD aren’t getting the preventive treatment they should. A Centers for Disease Control and Prevention report found that less than half of U.S. children ages 2 to 16 with SCD received the recommended screening for stroke. Furthermore, many of these children were not receiving hydroxyurea, the recommended treatment that can improve complications, anemia and quality of life.

In addition, the representation of Black Americans in the donor registry is very low, so patients often rely on siblings or parents, which may not provide the optimal match. This isn’t an issue with gene therapy because it uses the body’s own cells. However, the cost of the new treatments put it out of reach for most people with SCD.

Women with SCD face additional disparities. The U.S. has the highest rate of maternal mortality among 11 high-income countries, and Black women are more likely to die in pregnancy, childbirth or postpartum, according to Layla Van Doren, MD, hematologist at Yale Cancer Center and Smilow Cancer Hospital. “Maternal morbidity and mortality rates are even higher for pregnant persons with SCD,” she says. “Even with the recent FDA approval of two gene therapy products, there remain no established standard of care for preventing and managing complications for pregnant persons with SCD and no approved disease-modifying therapies.” 

Moreover, Van Doren points to research that has shown a relationship between vaso-occlusive events and menstruation. Menstrual blood loss can also make SCD-related anemia worse. She is involved in a study surveying SCD patients about how menstruation affects their pain events and health care utilization. 

Van Doren found that while most women who completed the survey had menstrual-related pain and menstrual-associated sickle cell pain, most were not taking hormone therapy. “Contraception not only provides control of unintended pregnancy but can also lead to decreased blood loss and management of menstrual-related sickle cell pain,” she says. 

Van Doren says sometimes patients might not even make the connection that their vaso-occlusive events are related to menstruation. “It is important for providers to ask because there are treatment options to help alleviate these symptoms,” she says. 

Connections to Other Diseases

SCD research holds the potential to benefit not only patients with the disease but those with other conditions, too. For example, research suggests a potential link between SCD and reduced susceptibility to HIV infection—individuals with SCD have a lower prevalence of HIV infection compared to the general population, though SCD does not offer complete protection. 

By studying the mechanisms that might lead to a reduced susceptibility to infection, “we might find some interesting pathways which can actually help to protect people from infection,” says Sergei Nekhai, PhD, medicine, microbiology and pharmacology professor at Howard University. 

Previous research indicates that a factor on certain immune cells, a protein called CCR5 that HIV-1 uses to infect these cells, is mutated on the immune cells in people with European ancestry, which may help protect against HIV-1 infection. But this is not the case for SCD patients, who, as Nekhai’s research showed, might suppress HIV-1 infection because of the upregulation of innate antiviral factors driven by changes in iron metabolism, hypoxia and production of interferon.

Advances in SCD research also provide clues for a similar disease: beta thalassemia, which is also an inherited blood disorder that affects the structure and function of red blood cells. “The same genetic treatments that are effective for sickle cell disease are also effective for beta thalassemia. So, there is hope that we can develop a treatment for one and use it on the other disease,” Sharma says.

More to Learn

Since the groundbreaking discovery in 1956 of the gene mutation responsible for SCD, our understanding of this condition has grown tremendously. Researchers have made significant strides in diagnosis, treatment options and overall disease management. However, there’s still much more to learn.

“The biggest question in the field is what defines the severity of manifestation of this disease,” Bogdanova says. “This is a monogenic disease, but we have patients with the same point mutation, and some of them are completely asymptomatic and some of them are dying early or spend life in pain. What is the difference between these two groups of people? That remains unclear.”

This article was originally published in the May 2024 issue of The Physiologist Magazine. Copyright © 2024 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.