Paradoxical Increase of Neurofilaments in SMA Patients Treated with Onasemnogene Abeparvovec-xioi

Overview

Journal Front Neurol

Specialty Neurology

Date 2024 Jan 1

PMID 38162454

Authors

Marina Flotats-Bastardas

Lisa Bitzan

Charlotte Grell

Kyriakos Martakis

Benedikt Winter

Michael Zemlin

Claudia D Wurster

Zeljko Uzelac

Claudia Weiss

Andreas Hahn

Affiliations

Soon will be listed here.

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.

References

Baranello G, Darras B, Day J, Deconinck N, Klein A, Masson R . Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021; 384(10):915-923. DOI: 10.1056/NEJMoa2009965. View

Wurster C, Steinacker P, GuNTHER R, Koch J, Lingor P, Uzelac Z . Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J Neurol. 2019; 267(1):36-44. DOI: 10.1007/s00415-019-09547-y. View

Darras B, Crawford T, Finkel R, Mercuri E, De Vivo D, Oskoui M . Neurofilament as a potential biomarker for spinal muscular atrophy. Ann Clin Transl Neurol. 2019; 6(5):932-944. PMC: 6530526. DOI: 10.1002/acn3.779. View

Milella G, Introna A, DErrico E, Fraddosio A, Scaglione G, Morea A . Cerebrospinal Fluid and Clinical Profiles in Adult Type 2-3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience. Clin Drug Investig. 2021; 41(9):775-784. PMC: 8390404. DOI: 10.1007/s40261-021-01071-0. View

Finkel R, Mercuri E, Darras B, Connolly A, Kuntz N, Kirschner J . Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18):1723-1732. DOI: 10.1056/NEJMoa1702752. View

Tukov F, Mansfield K, Milton M, Meseck E, Penraat K, Chand D . Single-Dose Intrathecal Dorsal Root Ganglia Toxicity of Onasemnogene Abeparvovec in Cynomolgus Monkeys. Hum Gene Ther. 2022; 33(13-14):740-756. PMC: 9347375. DOI: 10.1089/hum.2021.255. View

Pechmann A, Konig K, Bernert G, Schachtrup K, Schara U, Schorling D . SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet J Rare Dis. 2019; 14(1):18. PMC: 6341722. DOI: 10.1186/s13023-019-0998-4. View

Ziegler A, Wilichowski E, Schara U, Hahn A, Muller-Felber W, Johannsen J . [Recommendations for gene therapy of spinal muscular atrophy with onasemnogene abeparvovec-AVXS-101 : Consensus paper of the German representatives of the Society for Pediatric Neurology (GNP) and the German treatment centers with collaboration of...]. Nervenarzt. 2020; 91(6):518-529. DOI: 10.1007/s00115-020-00919-8. View

Mazzone E, Mayhew A, Montes J, Ramsey D, Fanelli L, Dunaway Young S . Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle Nerve. 2016; 55(6):869-874. DOI: 10.1002/mus.25430. View

10.

Verde F, Steinacker P, Weishaupt J, Kassubek J, Oeckl P, Halbgebauer S . Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2018; 90(2):157-164. DOI: 10.1136/jnnp-2018-318704. View

11.

Finkel R, Hynan L, Glanzman A, Owens H, Nelson L, Cone S . The test of infant motor performance: reliability in spinal muscular atrophy type I. Pediatr Phys Ther. 2008; 20(3):242-6. DOI: 10.1097/PEP.0b013e318181ae96. View

12.

Nitz E, Smitka M, Schallner J, Akgun K, Ziemssen T, von der Hagen M . Serum neurofilament light chain in pediatric spinal muscular atrophy patients and healthy children. Ann Clin Transl Neurol. 2021; 8(10):2013-2024. PMC: 8528467. DOI: 10.1002/acn3.51449. View

13.

De Vivo D, Bertini E, Swoboda K, Hwu W, Crawford T, Finkel R . Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019; 29(11):842-856. PMC: 7127286. DOI: 10.1016/j.nmd.2019.09.007. View

14.

Lunn M, Wang C . Spinal muscular atrophy. Lancet. 2008; 371(9630):2120-33. DOI: 10.1016/S0140-6736(08)60921-6. View

15.

Pino M, Rich K, Kolb S . Update on Biomarkers in Spinal Muscular Atrophy. Biomark Insights. 2021; 16:11772719211035643. PMC: 8371741. DOI: 10.1177/11772719211035643. View

16.

Pera M, Coratti G, Forcina N, Mazzone E, Scoto M, Montes J . Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol. 2017; 17(1):39. PMC: 5324197. DOI: 10.1186/s12883-017-0790-9. View

17.

Olsson B, Alberg L, Cullen N, Michael E, Wahlgren L, Kroksmark A . NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol. 2019; 266(9):2129-2136. PMC: 6687695. DOI: 10.1007/s00415-019-09389-8. View

18.

Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L . Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995; 80(1):155-65. DOI: 10.1016/0092-8674(95)90460-3. View

19.

Mendell J, Al-Zaidy S, Shell R, Arnold W, Rodino-Klapac L, Prior T . Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18):1713-1722. DOI: 10.1056/NEJMoa1706198. View

20.

Swoboda K, Scott C, Crawford T, Simard L, Reyna S, Krosschell K . SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010; 5(8):e12140. PMC: 2924376. DOI: 10.1371/journal.pone.0012140. View