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
N1 - Publisher Copyright:
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
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 - http://www.scopus.com/inward/record.url?scp=85127708440&partnerID=8YFLogxK
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 -