Bone marrow transplant in teen years may lower stroke risk in SCD
Damage to arteries continued in adult-equivalent mice in disease model
Undergoing a bone marrow transplant during adolescence may reduce the risk of stroke in people with sickle cell disease (SCD), while waiting until adulthood is unlikely to mitigate this risk, a mouse study suggests.
“We saw that if you wait until after the vasculature is damaged to do this procedure, the tissue doesn’t bounce back,” Manu Platt, PhD, the study’s corresponding author at the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health (NIH), said in an institute news release. “Down the line, this could be another key piece of information that is a motivator for earlier interventions.”
The study, “Bone marrow transplant protects mice from sickle cell-mediated large artery remodeling,” was published in Science Translational Medicine.
SCD, damaging to blood vessels in the brain, carries a stroke risk
Sickle cell is caused by mutations in a gene that provides instructions to make a component of hemoglobin, the protein that red blood cells use to carry oxygen in the bloodstream. The mutated hemoglobin tends to clump in red blood cells, deforming them into the sickle-like shape that gives the disease its name. These misshapen cells tend to get trapped in blood vessels, blocking blood flow and causing complications.
Arteries, the blood vessels that carry oxygen-rich blood through the body, progressively become damaged in people with SCD. Artery damage in the brain can set the stage for strokes. Studies suggest that more than 1 in 10 SCD patients will experience a stroke with obvious symptoms before they turn 20, and that more than 1 in 3 may experience a so-called silent stroke, one without obvious symptoms, before the age of 14.
Within the body, new blood cells are constantly being produced by stem cells found in the bone marrow. A potentially curative treatment for SCD is a bone marrow transplant (also known as a stem cell transplant), where healthy stem cells harvested from a donor are transplanted into a patient to restore their ability to make new blood cells that don’t carry the disease-causing mutation.
Two gene therapies, Casgevy (exagamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel), recently were approved in the U.S. and elsewhere for SCD. These treatments allow patients to receive engineered stem cells that can give rise to red blood cells capable of producing a functional version of hemoglobin without the need for a donor. However, a bone marrow transplant still would be required to deliver the genetically modified stem cells to patients.
A bone marrow transplant is a very intensive procedure that carries substantial risks. Prior to the transplant itself, patients must complete a conditioning regimen that typically entails use of powerful chemotherapy agents or radiation therapy to wipe out faulty stem cells and make room for the new stem cells to grow. For this reason, a stem cell transplant is generally reserved for patients whose severe SCD symptoms aren’t well controlled with standard medications.
Even though a bone marrow transplant could be a cure for SCD, patients may still experience complications stemming from artery damage. Previous research has suggested that a sizable fraction of adults with SCD will experience a stroke despite having gone through a bone marrow transplant. It hasn’t been clear, however, whether the timing of the transplant affects stroke risk.
Study points to age at transplant as possibly crucial in stopping damage
Scientists at the NIH office and at Georgia Institute of Technology conducted a series of experiments in an SCD mouse model. Some of the mice underwent a bone marrow transplant at 2 months of age, which is roughly equivalent to teenage years in people. Other mice underwent the procedure when they were 4 months old, the equivalent of adulthood in humans.
In this mouse model, arteries in the brain tend to get wider over time, while artery walls progressively get thinner. These changes are indicative of artery damage that can set the stage for stroke.
When a bone marrow transplant was performed when animals were 2 months old, the researchers found that arteries still showed some signs of damage, but the damage didn’t appear to worsen over time following the transplant. By contrast, when the transplant wasn’t done until mice reached 4 months old, artery damage continued to worsen after the procedure.
“This work … demonstrates that the timing of [bone marrow transplant] is crucial in mitigating sickle cell-induced large artery remodeling,” the researchers wrote.
Scientists focused mainly on blood vessels in the brain that are related to stroke, though they noted that an early transplant also seemed to lessen damage to arteries in other parts of the body, such as the liver. They are planning further studies to examine these effects.
“The arteries go everywhere, right? If there’s arterial damage somewhere due to this [blood] disease, then we want to see if earlier transplants can make a difference,” Platt said.
About the Author
