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

the SMArtCARE consortium

doi:10.1111/ene.15331

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

the SMArtCARE consortium

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.

Original language	English
Journal	European Journal of Neurology
Volume	29
Issue number	7
Pages (from-to)	2084-2096
Number of pages	13
ISSN	1351-5101
DOIs	https://doi.org/10.1111/ene.15331
Publication status	Published - 07.2022

Funding

D.C.S. has participated in workshops sponsored by Biogen and Roche, and has received compensation for consulting services from Pfizer. H.K. serves on a scientific advisory board for Avexis and has received travel and received speaker honoraria from Biogen, Pfizer, Roche, and Sanofi‐Aventis. A.P. has received compensation for advisory boards, training activities, and research grants from Novartis Gene Therapies and Biogen. B.W. is chair of the scientific advisory board of SMA Europe, and has received speaker honoraria from Biogen and Novartis/Avexis for scientific talks at workshops, seminars, and video conferences. J.K. has received research funding and/or compensation for presentations and consulting services from Avexis, Biogen, Novartis, and Roche. U.S.‐S. has received honoraria for presentations and consulting services from Avexis, Novartis, Biogen, and Roche. H.L. has received compensation for consultancy and financial support for research projects and clinical trials from Amplo Biotechnology, AMO Pharma, Biogen, Desitin, Fulcrum Therapeutics, GW Pharma, KYE Pharmaceuticals, Milo Biotechnology, Pfizer, PTC Therapeutics, Hoffman‐La Roche Limited, Sanofi‐Genzyme, Santhera, Sarepta, Satellos, and Ultragenyx. A.R. has received compensation for presentations and training activities from Sanofi‐Genzyme, and has received research funding from AMO Pharma. None of the other authors has any conflict of interest to disclose. The work of D.C.S. was supported by the German Society of Pediatric Neurology (Gesellschaft für Neuropädiatrie). A.P. was supported by the Berta‐Ottenstein clinician scientist program of the University of Freiburg. 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 study was supported by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein‐Westfalen, the Regierenden Bürgermeister von Berlin–Senatskanzlei Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung. 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). The work of D.C.S. was supported by the German Society of Pediatric Neurology (Gesellschaft für Neuropädiatrie). A.P. was supported by the Berta-Ottenstein clinician scientist program of the University of Freiburg. 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 study was supported by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierenden Bürgermeister von Berlin–Senatskanzlei Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung. 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). We thank all patients participating in this study; and Swantje Hertel, Fabian Förster, and Carmen Kopp for their expert technical assistance. This project was supported by the German Society of Pediatric Neurology. Open Access funding enabled and organized by Projekt DEAL. We thank all patients participating in this study; and Swantje Hertel, Fabian Förster, and Carmen Kopp for their expert technical assistance. This project was supported by the German Society of Pediatric Neurology. Open Access funding enabled and organized by Projekt DEAL.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
Centers: Center for Neuromuscular Diseases

Access to Document

10.1111/ene.15331

Cite this

@article{e7336f0738ad4891a538ba74c97e1471,

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

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.",

author = "\{the SMArtCARE consortium\} and Schorling, \{David C.\} and Heike K{\"o}lbel and Andreas Hentschel and Astrid Pechmann and Nancy Meyer and Brunhilde Wirth and Roman Rombo and Albert Sickmann and Janbernd Kirschner and Ulrike Schara-Schmidt and Hanns Lochm{\"u}ller and Andreas Roos and Abele, \{Thea Beatrice\} and Barbara Andres and Daniela Angelova-Toshkina and Petra Baum and Tobias Baum and Matthias Baumann and Manuela Baumgartner and Ute Baur and Benedikt Becker and Bettina Behring and G{\"u}nther Bernert and Theresa Birsak and Julia Bellut and Astrid Bertsche and Markus Blankenburg and Astrid Blaschek and Nathalie Braun and Sarah Braun and Nadine Burgenmeister and Nicole Claus and Isabell Cordts and \{de Vries\}, Heike and Timo Deba and Marina, \{Adela Della\} and Jonas Denecke and Marcus Deschauer and Katharina D{\"o}rnbrack and Joenna Driemeyer and Matthias Eckenweiler and Astrid Eisenk{\"o}lbl and Barbara Fiedler and Michal Fischer and Marina Flotats-Bastardas and Maren Freigang and Johannes Friese and Julian Grosskreutz and Thorsten Langer and Andreas Ziegler",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. European Journal of Neurology published by John Wiley \& Sons Ltd on behalf of European Academy of Neurology.",

year = "2022",

month = jul,

doi = "10.1111/ene.15331",

language = "English",

volume = "29",

pages = "2084--2096",

journal = "European Journal of Neurology",

issn = "1351-5101",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "7",

}

TY - JOUR

T1 - Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy

AU - the SMArtCARE consortium

AU - Schorling, David C.

AU - Kölbel, Heike

AU - Hentschel, Andreas

AU - Pechmann, Astrid

AU - Meyer, Nancy

AU - Wirth, Brunhilde

AU - Rombo, Roman

AU - Sickmann, Albert

AU - Kirschner, Janbernd

AU - Schara-Schmidt, Ulrike

AU - Lochmüller, Hanns

AU - Roos, Andreas

AU - Abele, Thea Beatrice

AU - Andres, Barbara

AU - Angelova-Toshkina, Daniela

AU - Baum, Petra

AU - Baum, Tobias

AU - Baumann, Matthias

AU - Baumgartner, Manuela

AU - Baur, Ute

AU - Becker, Benedikt

AU - Behring, Bettina

AU - Bernert, Günther

AU - Birsak, Theresa

AU - Bellut, Julia

AU - Bertsche, Astrid

AU - Blankenburg, Markus

AU - Blaschek, Astrid

AU - Braun, Nathalie

AU - Braun, Sarah

AU - Burgenmeister, Nadine

AU - Claus, Nicole

AU - Cordts, Isabell

AU - de Vries, Heike

AU - Deba, Timo

AU - Marina, Adela Della

AU - Denecke, Jonas

AU - Deschauer, Marcus

AU - Dörnbrack, Katharina

AU - Driemeyer, Joenna

AU - Eckenweiler, Matthias

AU - Eisenkölbl, Astrid

AU - Fiedler, Barbara

AU - Fischer, Michal

AU - Flotats-Bastardas, Marina

AU - Freigang, Maren

AU - Friese, Johannes

AU - Grosskreutz, Julian

AU - Langer, Thorsten

AU - Ziegler, Andreas

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85127708440

UR - https://www.mendeley.com/catalogue/9536efe7-f060-3e72-9fcb-1c64b80b753f/

U2 - 10.1111/ene.15331

DO - 10.1111/ene.15331

M3 - Journal articles

C2 - 35318785

AN - SCOPUS:85127708440

SN - 1351-5101

VL - 29

SP - 2084

EP - 2096

JO - European Journal of Neurology

JF - European Journal of Neurology

IS - 7

ER -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

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