Higher glial protein levels linked to better response to Spinraza in SMA
Study: New therapies could have positive impact on current treatments
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- Higher glial protein (GFAP) levels predict better Spinraza treatment response in SMA.
- GFAP and GDNF levels in the cerebrospinal fluid can help diagnose SMA.
- New therapies targeting glial cells and inflammation may enhance current SMA treatments.
Higher levels of the glial fibrillary acidic protein (GFAP) in the fluid around the brain and spinal cord are associated with a better clinical response to Spinraza (nusinersen) among people with spinal muscular atrophy (SMA), according to a recent study in Turkey.
Researchers analyzed whether levels of proteins derived from glial cells and proteins involved in neuroinflammation may aid in diagnosing and predicting treatment response in SMA. Glia, the most abundant cell type in the central nervous system (brain and spinal cord), support and protect neurons, while also shaping neural function.
According to researchers, these data “suggest that new therapies targeting glial cells … and the use of anti-inflammatory agents in SMA may have a positive effect on the clinical benefit of therapies that increase SMN levels.” SMN, which stands for survival motor neuron, is the protein produced in inadequate amounts in most SMA cases.
The study, “Detection of inflammation and glial cell-related biomarkers in adults with spinal muscular atrophy receiving nusinersen therapy,” was published in Neurological Sciences.
Researchers aimed to identify disease-specific biomarkers
Although SMA is well-known to lead to progressive loss of motor neurons, the specialized nerve cells that control movement, studies have supported a role for glial cells in SMA disease development.
In this study, researchers from Hacettepe University in Turkey aimed to identify molecules produced by glial cells and associated with neuroinflammation that could be used as disease-specific biomarkers to help diagnose SMA and predict clinical response to Spinraza. Neuroinflammation is an inflammatory response within the brain or spinal cord.
The study enrolled 24 adults with SMA — mainly males (79.2%) and with a mean age at disease onset of 8.7 years — and 12 controls without the disease. The majority had SMA type 3 (87.5%), while the others had SMA type 2. About one-third of the patients were able to walk before starting treatment. Patients initiated Spinraza at a mean age of 34.1 years.
Glial cell biomarkers in the cerebrospinal fluid, which bathes the brain and spinal cord, were collected before every treatment administration. For this study, the researchers evaluated biomarkers before treatment started and after 15 months, when maintenance dosing began.
SMA patients had elevated levels of total protein
Results demonstrated that SMA patients had significantly elevated levels of total protein (233.89 micrograms/mL vs. 192.67 micrograms/mL) and GFAP (10.43 nanograms/mL vs. 4.15 ng/mL) compared with controls. Interleukin-6 (IL-6), a signaling molecule involved in inflammation, was below detectable levels in controls but was detected in some SMA patients.
In addition, levels of glial cell-derived neurotrophic factor (GDNF), a protein critical for neuronal survival and function, were lower in SMA patients (4.03 ng/mL vs. 4.76 ng/mL). No differences were observed for YKL-40, another marker of inflammation. The levels of these proteins were not associated with disease duration or severity.
Further analysis demonstrated that GFAP levels above 6.12 ng/mL could help diagnose SMA with 95.1% accuracy, and GDNF levels below 4.3 ng/mL showed 86.1% accuracy. Combining GFAP with GDNF had a diagnostic accuracy of 99.7%.
New therapies targeting glial cells and anti-inflammatory agents may have a positive impact on the clinical utility of current treatments.
Under Spinraza treatment, IL-6 levels decreased by 95.7% and YKL-40 by 14.4% compared to before therapy. Additionally, GDNF levels increased by a mean of 7.93%. No changes were seen for GFAP or total protein levels.
Being younger at the start of treatment and having higher levels of GFAP and GDNF at study start could predict a stronger clinically meaningful response score, a measure of effects on motor function.
The risk of a poor clinical outcome increased with age and was lower with increasing GFAP levels before treatment. According to the researchers, these results suggest “a protective effect of elevated GFAP level.”
“New therapies targeting glial cells and anti-inflammatory agents may have a positive impact on the clinical utility of current treatments,” the scientists wrote, noting that the relatively small number of participants was one of the study’s limitations.
