(MEMPHIS, Tenn. – June 27, 2025) Gene therapy for sickle cell disease may help improve a major contributing factor to stroke risk in patients, reports a new study from St. Jude Children’s Research Hospital. Many people with sickle cell disease experience increased brain ischemia, where oxygen is not delivered properly to brain tissues, potentially leading to strokes. A part of the risk for these events comes from increased blood flow speed in the brain. Findings from three patients in a gene therapy clinical trial showed that gene therapy treatment significantly improved blood flow in the brain. These results demonstrate that people with these risk factors may benefit from gene therapy and should be considered for future clinical trials of gene therapy. The findings were published today in the American Journal of Hematology.
“We saw that after gene therapy, elevated blood flow speed in the brain came down to normal levels,” said corresponding author Akshay Sharma, MBBS, MSc, St. Jude Department of Bone Marrow Transplantation & Cellular Therapy. “This is the closest physiological evidence we have that gene therapy could be effective for patients with neurovascular disease who are at risk of or have had a stroke.”
Improving blood flow in the brain with gene therapy
A small but significant percentage of patients with sickle cell disease are at an increased risk of stroke due to the condition’s impact on blood flow in the brain. The crescent “sickle” shape of red blood cells characteristic of sickle cell disease cannot move through small blood vessels, including those in the brain. When those vessels become clogged, that region in the brain does not receive enough oxygen. To compensate for the lack of oxygen delivery, the body amps up the speed of blood flow, which increases the number of red blood cells moving through the brain and the total amount of available oxygen. This results in a decrease in the time oxygen molecules have to leave the red blood cells and enter the brain tissue, which can ultimately lead to brain ischemia. Brain ischemia is when a region of the brain is greatly deprived of oxygen, creating a significant risk factor for stroke, which can result in long-term damage.
“You can think of red blood cells filled with oxygen like a bus filled with people,” Sharma said. “If the bus is going too fast, passengers can’t get off the bus, and oxygen is not delivered. However, if the bus slows down so passengers can safely hop off, as happens when hemoglobin levels rise, then oxygen gets properly delivered to the brain tissues.”
The researchers measured gene therapy’s effect on the flow of blood in the brain using Magnetic Resonance Imaging (MRI). The study imaged the brains of three patients with sickle cell disease, before gene therapy and at one and two years after the treatment. Each patient’s brain blood flow improved significantly, decreasing anywhere from 22% to 43%, reaching mostly normal levels, which appeared stable over time.
Gene therapy is comparable or better than other treatments when it comes to brain blood flow
Results from the study compare well to previous studies measuring the impact of other treatments for sickle cell disease, including the drug hydroxyurea or blood transfusions. Hydroxyurea, the most common treatment for sickle cell disease, has only a small effect on brain blood flow, and while blood transfusions have a stronger positive impact on brain blood flow, the effect is transient because the patient must continually receive new transfusions for it to last. The researchers found gene therapy has a more substantial and long-lasting protective effect on the brain than either of these treatments.
Bone marrow transplants also normalize brain blood flow over the long term. While gene therapy and bone marrow transplantation were not compared directly in the study, the results suggest both treatments produce a similar return to normal blood flow in the brain that is durable over time.
This study of three patients provides preliminary evidence for gene therapy’s effect on stroke risk and requires follow-up studies to confirm the result. However, it adds to a growing body of evidence that gene therapy should be considered as a treatment option to protect brain health in patients with sickle cell disease.
The study provides support for new clinical trials for sickle cell disease gene therapy to include patients at risk for stroke. Historically, given the high-risk nature of their disease, these individuals have been excluded from gene therapy trials.
“We now have emerging data to at least evaluate the efficacy of gene therapy in patients with a risk of or history of stroke,” Sharma said. “Until now, we only had one option that had a long-term impact on blood flow in the brain: bone marrow transplantation. But now we may also have gene therapy as another viable method to protect against neurovascular disease in people with sickle cell disease.”
Authors and funding
The study’s other authors are Jane Hankins and Ranganatha Sitaram, St. Jude; Jaap-Jan Boelens and Maria Cancio, Memorial Sloan Kettering Cancer Center; Radhika Peddinti and James Labelle, University of Chicago Medicine; Lawrence Rispoli, Sarah Costa, Sharon Peled and Andrea Wiethoff, Novartis Institutes for Biomedical Research; and Sarah Sloan, Novartis Pharma AG.
The study was supported by Novartis Pharmaceuticals Corporation, USA.
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