Protein changes may help explain Spinraza response in SMA
Treatment with Spinraza (nusinersen) was linked to measurable changes in a range of cerebrospinal fluid (CSF) biomarkers in people with spinal muscular atrophy (SMA), some of which were associated with improvements in motor function, according to a review of published studies.
Among the protein changes seen in CSF, the liquid that surrounds the brain and spinal cord, markers of neurodegeneration, including NfL, pNF-H, and tau, appeared to show associations with treatment response, particularly in earlier or more severe disease stages.
CSF markers may help track treatment response
“Further large-scale, standardized, and longitudinal studies are required to validate candidate biomarkers and to clarify their integration with motor function assessments in monitoring treatment response in SMA,” the scientists wrote.
The study, “Proteomic alterations in cerebrospinal fluid of spinal muscular atrophy patients undergoing nusinersen therapy: a systematic review and meta-analysis of potential biomarkers of treatment response,” was published in Neurological Sciences.
Most cases of SMA are caused by inherited mutations or deletions in the SMN1 gene, which lead to a deficiency in SMN, a protein essential for the health of nerve cells in the spinal cord and brain stem that control muscle movement, called motor neurons. Clinically, this results in severe muscle atrophy (shrinkage), low muscle tone, and in severe cases, breathing problems.
Spinraza is a disease-modifying therapy for SMA. Delivered via injections into the spinal canal, it works by boosting SMN production. Clinical trials and real-world data consistently show that starting Spinraza as early as possible leads to better motor and developmental outcomes.
Despite these benefits, predicting how a patient will respond to the therapy remains challenging. While factors such as age and motor abilities at the start of treatment can serve as broad outcome indicators, there are no reliable SMA-specific biomarkers to track treatment effectiveness over time.
Because Spinraza is administered directly into the spinal canal, the CSF is a particularly relevant medium to study when looking for useful biomarkers.
Review examines protein changes after Spinraza
With this in mind, scientists in Jordan and Turkey conducted a review of 21 published studies reporting changes in the CSF proteome, or the full set of proteins present in CSF, across 890 SMA patients receiving Spinraza therapy.
Two studies examined overall CSF protein profiles. Patients with stable motor function after treatment showed increased levels of CPE-NF-alpha1, NPTX1, SEMA7A, and COL6A1, and lower levels of CDH18 compared with those who improved. A late rise in overall CSF protein levels was observed in SMA type 2 and type 3, but not in SMA type 1.
Eleven studies found that NfL and pNF-H, markers of nerve fiber damage, were elevated in untreated SMA and decreased after Spinraza treatment. Earlier treatment also was associated with greater decreases and better motor outcomes. Some studies reported complex patterns in which early reductions in NfL were followed by later increases, reflecting individual differences in biomarker response.
In SMA type 1, changes in alpha-synuclein and BACE-1 were linked to motor improvement, while alpha-synuclein changes appeared smaller in patients with longer disease duration. Amyloid-beta peptide, which is involved in nervous system function, exhibited a pattern of an early increase, brief stabilization, and a subsequent rise during treatment.
Tau, a marker of nerve fiber damage, was highest before treatment in SMA type 1 patients and declined significantly with Spinraza, particularly when treatment was initiated earlier. In children, reductions in tau with each dose correlated strongly with motor improvement. In adults with milder SMA, tau levels were generally within normal ranges, although one study in adults with SMA type 3 reported slight increases during early treatment.
Immune and metabolic markers also shifted
Five studies examined immune signaling proteins in the CSF. In children, levels of several immune proteins — interleukin-4 (IL-4), IL-22, IL-23, IL-33, and IFN-gamma — declined significantly after six months of treatment, while IL-6 and IL-17A declined in adults.
The immune system protein MCP-1 showed a gradual increase over time and was the only biomarker with a significant association with improved motor function, independent of age, “highlighting its potential as a clinically relevant biomarker,” the team noted.
Apolipoproteins A1 and E, along with transthyretin — proteins involved in lipid, or fat-like molecule, transport and metabolism in the nervous system — increased significantly after six months of treatment. SMA patients were found to have altered levels and impaired function of HDL-like particles, which are lipid carriers, in CSF, and these changes were reported to move toward normal following Spinraza treatment.
The six-minute walk test (6MWT), a standardized measure of walking ability and endurance, showed variable but clinically significant improvements following Spinraza therapy. Lower NfL levels in the CSF correlated with better 6MWT performance at a later time point (eight months). Reductions in neurodegenerative CSF biomarkers also paralleled improvements in motor function, as assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE).
Cathepsin D, an enzyme involved in protein breakdown, showed age-related patterns during treatment, with increases in younger patients and declines in older patients. These differences may reflect the effect of developmental stage on tissue remodeling. Among connective tissue proteins, increases in COL1A2 and decreases in SEMA6A were linked to better Spinraza responses, particularly in SMA type 3.
“Our results consolidate evidence from 21 studies evaluating a wide range of molecular biomarkers,” the scientists wrote. “CSF proteomic biomarkers should be considered exploratory, and their integration with established clinical outcome measures such as HFMSE and 6MWT warrants further investigation before routine clinical application.”
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