Brain fluid biomarkers may help predict Spinraza efficacy in SMA
Some molecules in metabolism differed between responders, nonresponders
Molecular markers in the liquid that surrounds the brain and spinal cord, called the cerebrospinal fluid (CSF), may help predict how well people with type 2 or 3 spinal muscular atrophy (SMA) respond to Spinraza (nusinersen), a study reports.
The study’s researchers found that certain CSF molecules involved in metabolism, which is the process of breaking down substances to generate energy, differed between those who responded to treatment and those who didn’t. These metabolites also varied by SMA type, suggesting distinct biological processes may influence Spinraza’s effectiveness.
Shifts in key metabolite levels could alter the response to the therapy, the researchers proposed. “The results of this study may guide the development of adjunctive therapies to enhance nusinersen efficacy,” they wrote. The study, “Cerebrospinal fluid metabolomics reveals predictive biomarkers of nusinersen therapy efficacy in type II and type III spinal muscular atrophy patients,” was published in Neurological Sciences.
SMA is primarily caused by mutations in the SMN1 gene, which provides instructions for producing the survival motor neuron (SMN) protein. A deficiency of this protein leads to the degeneration of the nerve cells responsible for controlling muscle movement, or motor neurons.
The disease is classified into different types based on the age of onset and the severity of its symptoms. Type 1 is the most severe and most common form, typically appearing in infants within the first six months of life. In type 2, symptoms such as difficulty sitting and walking usually emerge between 6 and 18 months. It’s generally more severe than type 3, which tends to appear after 18 months and often allows for independent walking, at least initially.
Spinraza is approved for all types. It works by modifying the splicing of the SMN2 gene, a backup gene to SMN1, to increase production of full-length, functional SMN protein. On its own, SMN2 produces only small amounts of the protein, but Spinraza helps more of it be made, thereby improving motor neuron survival and easing symptoms.
Predicting Spinraza’s effectiveness
Predicting how well a person with SMA will respond to Spinraza can be challenging because the disease varies widely from person to person. Some studies show that early treatment leads to better results, while others have found no major difference between children and adults. Also, while the number of SMN2 gene copies is linked to disease severity, that doesn’t explain how someone will respond to treatment. Other genetic factors may also play a role, which also makes it difficult to predict how effective Spinraza will be for each person.
Metabolomics, the study of small molecules (metabolites) in the body, can help to better understand diseases like SMA. By analyzing different metabolites in samples such as the CSF, researchers can find new biomarkers that show how the disease is progressing or how well a treatment is working.
Here, researchers studied 28 children with type 2 SMA and 14 with type 3. Along with a metabolomic analysis, they collected medical information and all the participants received scores on the Hammersmith Functional Motor Scale Expanded (HFMSE), which measures the ability to complete various activities.
The participants received four doses of Spinraza over two months initially, followed by maintenance doses every four months. Anyone whose HFMSE scores improved by at least 3 points — half the participants in each group — was considered a Spinraza responder.
Forty-seven metabolites differed significantly between responders and nonresponders in the type 2 group. Previous studies have linked one of these — 1-arachidonoyl-2-hydroxy-sn-glycero-3-phosphate — to several other neurodegenerative diseases and researchers found it was “negatively related to the efficacy of nusinersen” and could predict the efficacy of Spinraza in this group. In the type 3 group, 109 metabolites differed significantly between responders and nonresponders.
A closer look at these metabolites showed that different body processes might be linked to how well Spinraza works in each type. In responders with SMA type 2, the CSF metabolites were mostly related to hormones, cell signaling, amino acids, vitamins, and in processing certain molecules that help make DNA and energy, called purines. In type 3 responders, the metabolites were mainly linked to amino acids, purines, and fats called phospholipids.
For nonresponders, increasing activity in these metabolic pathways “may have a synergistic effect on [Spinraza] treatment, ultimately resulting in a favorable therapeutic outcome,” the researchers wrote.
Within each type, researchers built statistical models that could predict with reasonable accuracy if a participant would respond, depending on metabolite levels.
Two metabolites involved in brain inflammation had significant negative correlations with HFMSE scores — that is, poorer motor function corresponded to higher levels of the metabolites. Specifically, N-myristoyl arginine was negatively correlated with HFMSE changes in type 2 patients, while 1,1,1,2,2-pentafluoro-7-phenylheptan-3-one was negatively correlated with HFMSE changes in type 3 patients.
“Neuroinflammation may affect the therapeutic effect of nusinersen, and residual neuroinflammation may become a new therapeutic target,” wrote the researchers, who suggest follow-up studies of CSF metabolites in larger groups, as the present study included a relatively small sample.
If validated, the metabolites could help predict if patients will respond to Spinraza and possibly offer methods to enhance its efficacy.
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