Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy

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• dc.contributor.author Schorling, David
• dc.contributor.author Kölbel, Heike
• dc.contributor.author Hentschel, Andreas
• dc.contributor.author Pechmann, Astrid
• dc.contributor.author Meyer, Nancy
• dc.contributor.author Wirth, Brunhilde
• dc.contributor.author Rombo, Roman
• dc.contributor.author SMArtCARE consortium
• dc.contributor.author Sickmann, Albert
• dc.contributor.author Kirschner, Janbernd
• dc.contributor.author Schara-Schmidt, Ulrike
• dc.contributor.author Lochmüller, Hanns
• dc.contributor.author Roos, Andreas
• dc.date.accessioned 2022-05-25T10:14:55Z
• dc.date.available 2022-05-25T10:14:55Z
• dc.date.issued 2022
• dc.description Data de publicació electrònica: 23-03-2022
• dc.description.abstract Background and purpose: The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision-making remains challenging, underlining the persistent need for validated biomarkers. Methods: We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme-linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results: Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0-16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions: We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients.
• dc.description.sponsorship Funding: H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This work was also supported by a grant of the French Muscular Dystrophy Association (AFM-Téléthon;#21466) to A.R. The work of B.W. is supported by the German Research Foundation (Wi945/17-1, SFB 1451 [project-ID 431549029–A01] and GRK1960 [project ID 233886668]), the European Research Council under the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 956185 (SMABEYOND), and the Center for Molecular Medicine Cologne (project No C18)
• dc.format.mimetype application/pdf
• dc.identifier.citation Schorling DC, Kölbel H, Hentschel A, Pechmann A, Meyer N, Wirth B et al. Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy. Eur J Neurol. 2022 Mar 23. [Epub Ahead of Print]. DOI:10.1111/ene.15331
• dc.identifier.doi http://dx.doi.org/10.1111/ene.15331
• dc.identifier.issn 1351-5101
• dc.identifier.uri http://hdl.handle.net/10230/53261
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/956185
• dc.rights © 2022 David C. Schorling et al. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.other Atròfia muscular espinal -- Tractament
• dc.title Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion