NFL is a marker of treatment response in children with SMA treated with nusinersen.

Abstract

BACKGROUND:

Recently, the anti-sense oligonucleotide drug nusinersen was approved for spinal muscular atrophy (SMA) and our aim was to find a response marker for this treatment.

METHODS:

Twelve children with SMA type 1 and two copies of the SMN2 gene were included in a consecutive single-center study. The children were sampled for CSF at baseline and every time nusinersen was given intrathecally. The neuronal biomarkers NFL and tau and the glial biomarker GFAP were measured. Motor function was assessed using CHOP INTEND. Eleven similarly aged children, who were investigated to rule out neurological or infectious disease, were used as controls.

RESULTS:

Baseline levels of NFL (4598 ± 981 vs 148 ± 39, P = 0.001), tau (939 ± 159 vs 404 ± 86, P = 0.02), and GFAP (236 ± 44 vs 108 ± 26, P = 0.02) were significantly higher in SMA children than controls. Motor function improved by nusinersen treatment in median 13 points corresponding to 5.4 points per month of treatment (P = 0.001). NFL levels typically normalized ( < 380 pg/ml) between the fourth and fifth doses [- 879.5 pg/mL/dose, 95% CI (- 1243.4, - 415.6), P = 0.0001], tau levels decreased [- 112.6 pg/mL/dose, 95% CI (- 206-7, - 18.6), P = 0.01], and minor decreases in GFAP were observed [- 16.9 pg/mL/dose, 95% CI (- 22.8, - 11.2), P = 0.02] by nusinersen treatment. Improvement in motor function correlated with reduced concentrations of NFL (rho = - 0.64, P = 0.03) and tau (rho = - 0.85, P = 0.0008) but not GFAP.

CONCLUSIONS:

Nusinersen normalized the axonal damage marker NFL and correlated with motor improvement in children with SMA. NFL may, therefore, be a novel biomarker to monitor treatment response early in the disease course.

• Authors: Bob Olsson, Lars Alberg, Nicholas C Cullen, Eva Michael, Lisa Wahlgren, Anna-Karin Kroksmark, Kevin Rostasy, Kaj Blennow, Henrik Zetterberg, Már Tulinius
• Journal: Journal of neurology (J Neurol) Vol. 266 Issue 9 Pg. 2129-2136 (Sep 2019) ISSN: 1432-1459 [Electronic] Germany
• PMID: 31123861 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Neurofilament Proteins
• Oligonucleotides
• neurofilament protein L
• nusinersen

Topics

• Biomarkers (cerebrospinal fluid)
• Child, Preschool
• Dose-Response Relationship, Drug
• Female
• Humans
• Infant
• Male
• Neurofilament Proteins (cerebrospinal fluid)
• Oligonucleotides (therapeutic use)
• Spinal Muscular Atrophies of Childhood (cerebrospinal fluid, drug therapy)
• Treatment Outcome