Spinraza treatment restores lipid balance in CSF of SMA children
Small study looks at treatment's effect on metabolic changes seen in SMA
Spinraza (nusinersen) treatment may help restore balance to the levels of some lipids, fat-like molecules that are lower in the cerebrospinal fluid (CSF) of children with spinal muscular atrophy (SMA) than in healthy children, a small study found.
Cerebrospinal fluid, or CSF, is the fluid around the brain and spinal cord. The scientists looked at CSF samples from children with SMA, some of whom had started Spinraza treatment, and from healthy children. They found that Spinraza may help reverse some of the widespread metabolic changes seen in SMA children.
The study, “Multi-omics profiling in spinal muscular atrophy (SMA): investigating lipid and metabolic alterations through longitudinal CSF analysis of Nusinersen-treated patients,” was published in the Journal of Neurology.
SMA is a genetic disease that damages motor neurons, the nerve cells that control muscles. Because muscles don’t receive proper signals from motor neurons, they weaken over time, making movement, breathing, and swallowing increasingly more difficult. A previous study found that children with SMA processed lipids differently than healthy children.
The researchers, in Austria, noted that the SMA children had lower cholesterol and phospholipids, molecules that help cells maintain structure by keeping their membranes both flexible and robust. The transport of these lipids in the brain may be impaired, making nerve cells more prone to damage. They set out to investigate whether Spinraza may help restore metabolic balance in children with SMA.
Key lipids lower in SMA kids
Biogen’s Spinraza, the first approved disease-modifying treatment targeting the cause of SMA, helps slow or even stop the progressive muscle weakness that characterizes the disease. Injected into the spinal canal, it’s approved to treat all types of SMA in children and adults.
The study involved samples from 13 children (seven girls, six boys) with SMA. Five had SMA type 1, seven had SMA type 2, and one had SMA type 3. As controls for comparison, the study included samples from 15 age-matched healthy children (eight boys, seven girls).
Seven of the children with SMA were being treated with Spinraza at the study’s start. The other six were treatment-naïve; that is, they had never received treatment for SMA, but were started on Spinraza during the study. For the comparison, the researchers used samples collected after six months of starting treatment.
In the CSF of children with SMA, the level of key lipids like sphingolipids, triacylglycerols, and phospholipids was about half of that in healthy children, with free cholesterol decreasing by about 2.5-fold. In contrast, phosphatidylglycerols, lyso-phospholipids, and cholesteryl esters nearly doubled.
Treatment-naïve children showed clear differences compared with healthy children in the CSF and levels of its constituents, which were reduced after six months of treatment with Spinraza. There were no significant differences among the three different types of SMA.
Regardless of treatment, children with SMA had altered lipids, suggesting changes in the function of high-density-lipoprotein (HDL)-like particles. HDL-like particles are molecules similar to good cholesterol; they help transport lipids in the blood “and play a major role in neuroprotection and neuronal health,” the scientists wrote.
“Since cholesterol metabolism in the [central nervous system, the brain and spinal cord] is separate from that of the periphery, the only lipoproteins present in the CNS are HDL-like particles,” the researchers wrote. “This shift was particularly evident in [treatment-naïve] patients, but also to some extent in patients undergoing [treatment with Spinraza].”
The researchers performed a cholesterol efflux assay to measure how well the particles remove cholesterol from cells. Children with SMA had about 20% lower HDL function, but Spinraza improved it by 9%, bringing it closer to its physiological (normal) level.
Treatment with Spinraza “was observed to reverse disease-specific profile changes toward a physiological state, potentially explicable by restoring HDL function,” the researchers wrote. However, they added, while “treatment is beneficial, it does not completely reverse metabolic lipid alterations.”
Further “studies will help to show whether an adapted treatment protocol with higher doses of [Spinraza] can further enhance its role as a potent disease modulator by fully restoring metabolic perturbations to a physiologic state,” the researchers concluded.
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