Paradoxical increase of neurofilaments in SMA patients treated with onasemnogene abeparvovec-xioi

Marina Flotats-Bastardas; Lisa Bitzan; Charlotte Grell; Kyriakos Martakis; Benedikt Winter; Michael Zemlin; Claudia D Wurster; Zeljko Uzelac; Claudia Weiß; Andreas Hahn

doi:10.3389/fneur.2023.1269406

Paradoxical increase of neurofilaments in SMA patients treated with onasemnogene abeparvovec-xioi

Front Neurol. 2023 Dec 13:14:1269406. doi: 10.3389/fneur.2023.1269406. eCollection 2023.

Authors

Affiliations

¹ Department of Pediatric Neurology, Saarland University Medical Center, Saarland University, Homburg, Germany.
² Department of Pediatric Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³ Department of Child Neurology, Justus Liebig University Giessen, Giessen, Germany.
⁴ Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁵ Department of Child Neurology, Mannheim University, Mannheim, Germany.
⁶ Department of General Pediatrics and Neonatology, Saarland University Medical Center, Saarland University, Homburg, Germany.
⁷ Department of Neurology, Ulm University, Ulm, Germany.

Abstract

Background/objective: Neurofilament light chain (NfL) has been proposed as a biomarker reflecting disease severity and therapy response in children with spinal muscular atrophy type 1 and 2 (SMA1 and 2). The objective of this study was to examine how serum NfL changes after gene replacement therapy (GRT) with onasemnogene abeparvovec-xioi.

Methods: We measured NfL in serum probes from 19 patients (10 SMA 1 and 6 SMA 2; 15 previously treated with nusinersen or risdiplam; 12 male) before and at variable time points after GRT. These values were related to motor scores (CHOP-Intend, HFMSE and RULM).

Results: Median age at GRT was 19 months (range 2-46 months). Median NfL of all patients before GRT was 39 pg/ml (range 0-663 pg/ml; normal values <25 pg/ml), increased significantly to 297 pg/ml (range 61-1,696 pg/ml; p<0,002) 1 month after GRT, and decreased to 49 pg/ml (range 24-151 pg/ml) after 6 months. Subjects pre-treated with nusinersen or risdiplam had lower baseline NfL levels than naïve patients (p<0,005), but absolute increases of NfL were similar in both groups. While motor scores were improved in 14 out of 18 SMA patients (78%) 6 months after GRT NfL values differed not significantly from those measured at baseline (p = 0,959).

Conclusion: Serum NfL showed a paradoxical transient increase after GRT in both, pre-treated and naïve patients, which may reflect an immunological reaction in the CNS related to transfection of neuronal cells by AAV9. The clinical meaning of this increase should be assessed in future studies. Our findings encourage regular monitoring of NfL in OA treated patients.

Keywords: SMA; neurofilament; nusinersen; onasemnogene abeparvosec; risdiplam.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We acknowledge the support of Saarland University.