Gene therapy for sickle cell disease has demonstrated significant improvements in brain blood flow, potentially reducing stroke risk in patients with this inherited blood disorder, according to new research from St. Jude Children's Research Hospital published in the American Journal of Hematology.
The study examined three patients with sickle cell disease who received gene therapy treatment, measuring brain blood flow using Magnetic Resonance Imaging (MRI) before treatment and at one and two years post-therapy. Each patient showed substantial improvements, with brain blood flow decreasing by 22% to 43%, reaching mostly normal levels that remained stable over time.
"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, from St. Jude's 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."
Addressing Brain Ischemia and Stroke Risk
Many patients with sickle cell disease experience increased brain ischemia, where oxygen is not properly delivered to brain tissues, creating significant stroke risk. The characteristic crescent "sickle" shape of red blood cells cannot move efficiently through small blood vessels, including those in the brain. When these vessels become clogged, affected brain regions receive insufficient oxygen.
To compensate for reduced oxygen delivery, the body increases blood flow speed, which paradoxically creates additional problems. While faster flow increases the number of red blood cells moving through the brain and total available oxygen, it reduces the time oxygen molecules have to leave red blood cells and enter brain tissue, ultimately leading to brain ischemia.
Sharma explained the mechanism using an analogy: "You can think of red blood cells filled with oxygen like a bus filled with people. 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."
Superior Outcomes Compared to Standard Treatments
The gene therapy results compare favorably to existing sickle cell disease treatments. Hydroxyurea, the most common treatment, has only a small effect on brain blood flow. While blood transfusions produce stronger positive impacts on brain blood flow, the effect is transient, requiring continuous transfusions to maintain benefits.
The researchers found gene therapy provides more substantial and long-lasting protective effects on the brain than either hydroxyurea or blood transfusions. Bone marrow transplants also normalize brain blood flow over the long term, and while gene therapy and bone marrow transplantation were not directly compared in this study, results suggest both treatments produce similar, durable returns to normal brain blood flow.
Implications for Future Clinical Trials
This preliminary evidence supports expanding gene therapy clinical trials to include patients at risk for stroke. Historically, these high-risk individuals have been excluded from gene therapy trials due to the severity of their condition.
"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."
The study adds to growing evidence that gene therapy should be considered as a treatment option to protect brain health in patients with sickle cell disease. While the three-patient study provides preliminary evidence requiring follow-up studies for confirmation, it represents a significant step toward understanding gene therapy's potential in reducing stroke risk for this vulnerable patient population.
The research was supported by Novartis Pharmaceuticals Corporation and included collaborators from Memorial Sloan Kettering Cancer Center, University of Chicago Medicine, and Novartis research institutes.
