Inflammatory Protein IL-8 May Predict Response to Spinraza: Study
Lower IL-8 levels when starting Spinraza led to better outcomes over time
Children with spinal muscular atrophy (SMA) who have lower levels of an inflammatory protein called interleukin-8 (IL-8) in the fluid surrounding the brain and spinal cord tend to respond better to treatment with Spinraza (nusinersen), a new study suggests.
The findings indicate that IL-8 is a better predictor of treatment response than neurofilament light chain, or NfL, a well-studied protein marker of nerve damage.
The study, “CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy,” was published in Neurotherapeutics.
Spinraza and other disease-modifying therapies have revolutionized SMA care
Spinraza was the first disease-modifying therapy for SMA to be widely approved. The introduction of Spinraza and other treatments has revolutionized SMA care, with patients achieving never-before-seen outcomes.
Like with any medication, responses to treatment with Spinraza vary from person to person. A team of scientists in the U.S. conducted an analysis to identify markers that could help predict the response to treatment.
Specifically, the scientists analyzed the content of patients’ cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord. Spinraza is administered via injection into the spine, and CSF samples can be collected during these injections.
The analysis included 49 CSF samples collected from 13 SMA patients. Nine of the patients were under the age of 2 years, and the other four were older.
Motor outcomes, as assessed with a standardized test called CHOP INTEND, were generally better among the younger patients.
The scientists first assessed levels in the CSF of the protein NfL, which is a structural protein in nerve cells that gets released when nerves are damaged.
In all patients, NfL levels decreased after starting on Spinraza, but in most cases, levels rose again several months later. Paradoxically, younger patients — who experienced a better response to treatment, as assessed by CHOP INTEND — had higher NfL levels at the start of treatment.
All in all, the data showed little clear association between NfL in the CSF and outcomes from treatment.
“Because higher baseline CSF NfL levels — hypothesized to reflect neurodegeneration — paradoxically associated with better baseline CHOP INTEND scores and its later levels rose with age, we sought to identify other CSF biomarkers correlated with disease severity and treatment response,” the researchers wrote.
“We hypothesized that CSF proteins involved in inflammation and neuronal activity may better correlate with individual response to [Spinraza] than NfL,” they said.
Statistical models showed that IL-8, a protein involved in driving inflammation, was significantly associated with CHOP INTEND scores over time; decreasing IL-8 levels over time tended to associated with better outcomes in motor function. IL-8 also correlated with compound muscle action potential (CMAP), a measure of electrical activity in muscle cells.
“The longitudinal linkage between IL-8 and independent clinical measures (global function and regional CMAP) supports this CSF protein as a candidate biomarker for SMA disease severity,” the researchers wrote.
Lower IL-8 levels when starting Spinraza were predictive of better outcomes
In subsequent analyses, the researchers found that lower IL-8 levels at the start of treatment were also predictive of better outcomes over time on CHOP INTEND and CMAP. By contrast, NfL levels at treatment initiation were not predictive of outcomes.
“Lower baseline IL-8 levels were additionally associated with better CHOP INTEND scores and CMAP regardless of treatment initiation age, but the difference diminished over time for younger children compared to older children,” the researchers wrote.
“These findings suggest CSF IL-8 as a more meaningful biomarker related to or downstream of neurodegeneration than NfL in SMA,” the team concluded.
The scientists noted that this study is limited by its small size, stressing a need for additional studies to verify the results. They also highlighted a need for more research into the role that IL-8 plays in SMA, and its potential use as a predictor of outcomes for other SMA treatments.
Spinraza is sold by Biogen, which was not involved in this study. The present work was funded by Emory University and the National Institutes of Health.