Protein Level Correlates With Pediatric SMA Severity, Treatment Response

The protein thrombospondin-4 (TSP4) is reduced in the cerebrospinal fluid (CSF) of children with spinal muscular atrophy (SMA) and may serve as a meaningful biomarker of disease and response to therapy, according to a new report.

The investigators found TSP4 levels appear to vary based on whether a child is symptomatic and whether they have had treatment.¹ The study was published in the Journal of Neurology.

The SMN2 gene is currently the primary biomarker for the disease, but it is not a reliable predictor of ongoing disease activity. | Image Credit: © Rochu_2008 - stock.adobe.com

SMA is characterized by a deficiency of survival of motor neuron (SMN) protein, which ultimately leads to progressive muscle weakness and atrophy. The SMN2 gene is currently the primary biomarker for the disease, according to corresponding author Tobias Ruck, MD, PhD, of Germany’s Heinrich Heine University Düsseldorf, and colleagues.

“Given that SMN2 constantly produces approximately 10% functional SMN protein, SMN2 copy number in the majority of patients inversely correlates with disease severity and onset and thus in the past stratifies for pre-symptomatic treatment,” they wrote.

Yet, while SMN2 copy number is a valuable biomarker of disease severity, the investigators said it is not a reliable predictor of ongoing disease activity.

“Particularly, it does not serve as an indicator of treatment response,” they said.

As newer therapies, such as nusinersen (Spinraza), risdiplam (Evrysdi), and the gene replacement therapy onasemnogene abeparvovec (Zolgensma) have become available, Ruck and colleagues said it has become important to better understand the different pathophysiological aspects of SMA, including the role of retrograde signaling from skeletal muscles and neuromuscular junctions (NMJs) in the disease.

The investigators wanted to look more closely at TSP4 because it is part of a protein family that participates in many biological functions. In 1995, soon after it was first discovered, researchers published a study showing that TSP4 plays an important role at the NMJ in mice.² The authors noted, though, that its expression varies at different ages.

Ruck and colleagues decided to assess TSP4 as a biomarker for SMA by analyzing CSF samples of 10 pediatric patients who were identified through a screening program in Germany.¹ Four of the patients were symptomatic; the other 6 had not yet shown symptoms. Ruck and colleagues found that TSP4 levels were significantly different between the 2 groups of patients. To validate those findings, the investigators then took 68 CSF samples from 9 adults and 24 children with SMA, 5 healthy adults and 13 healthy children (who acted as controls), and 17 children with other pediatric diseases (who acted as a second control group).

Those samples were then analyzed by enzyme-linked immunosorbent assay, which showed that TSP4 was decreased in pediatric patients with SMA, although it was not decreased in adults with the disease. Furthermore, children with other neurological disorders, but not SMA, also had no alteration in TSP4 levels.

To see whether the biomarker might help track response to therapy, investigators looked at the CSF TSP4 levels of children before and after their first dose of nusinersen. They found the therapy led to an increase of TSP4.

The investigators said their findings are encouraging, but also preliminary. They said further studies with larger, extended cohorts would be needed to fully validate TSP4 as a biomarker, including whether and why it may not be effective in adults.

“Taking the informative potential of TSP4 only in pediatric but not adult SMA-patients into consideration, one might speculate that this molecular observation is based on a development-dependent expression of the protein,” they added.

They added that future investigators should evaluate whether TSP4 also works as a marker of therapeutic response for other SMA therapies.

References

1. Dobelmann V, Roos A, Hentschel A, et al. Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy. J Neurol. Published online September 6, 2024. doi:10.1007/s00415-024-12670-0
2. Arber S, Caroni P. Thrombospondin-4, an extracellular matrix protein expressed in the developing and adult nervous system promotes neurite outgrowth. J Cell Biol. 1995;131(4):1083-1094. doi:10.1083/jcb.131.4.1083