2. Academic Validation
  3. Targeted Proteomics upon Treatment with Tofersen Identifies Novel Response Markers for Superoxide Dismutase 1-Linked Amyotrophic Lateral Sclerosis

Targeted Proteomics upon Treatment with Tofersen Identifies Novel Response Markers for Superoxide Dismutase 1-Linked Amyotrophic Lateral Sclerosis

  • Ann Neurol. 2025 Dec;98(6):1318-1334. doi: 10.1002/ana.70025.
Christina Steffke # 1 2 3,  Karthik Baskar # 2 3,  Franziska Bachhuber # 1,  Maximilian Wiesenfarth # 1,  Johannes Dorst 1,  Joachim Schuster 1 4,  Florian Schöberl 5,  Peter Reilich 5,  Martin Regensburger 6,  Alexander German 6,  René Günther 7 8,  Maximilian Vidovic 7,  Susanne Petri 9,  Thomas Meyer 10,  Tim Hagenacker 11,  Julian Grosskreutz 12,  Ute Weyen 13,  Patrick Weydt 14 15,  Thomas Haarmeier 16,  Paul Lingor 17 18 19,  Joachim Wolf 20,  Andreas Hermann 21 22,  Johannes Prudlo 22 23,  Kornelia Günther 1,  Antje Knehr 1,  Zeynep Elmas 1,  Zeljko Uzelac 1,  Simon Witzel 1,  Wolfgang Philipp Ruf 1 4,  Axel Freischmidt 1,  Ritchie Ho 24 25 26 27,  Albert C Ludolph 1 4,  Jochen H Weishaupt 1 28 29,  Hayrettin Tumani 1 4,  Patrick Oeckl 1 4,  David Brenner # 1 4 29,  Alberto Catanese # 2 4 30
Affiliations

Affiliations

  • 1 Department of Neurology, Ulm University, Ulm, Germany.
  • 2 Institute of Anatomy and Cell Biology, Ulm, Germany.
  • 3 International Graduate School, Ulm University, Ulm, Germany.
  • 4 German Center for Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany.
  • 5 Department of Neurology with Friedrich Baur Institute, LMU University Hospital, München, Germany.
  • 6 Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 7 Department of Neurology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
  • 8 German Center for Neurodegenerative Diseases (DZNE) Site Dresden, Dresden, Germany.
  • 9 Department of Neurology, Hannover Medical School, Hannover, Germany.
  • 10 Department of Neurology, Center for ALS and Other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • 11 Department of Neurology and Center for Translational Neuro and Behavioral Sciences (C-TNBS), University Hospital Essen, Essen, Germany.
  • 12 Precision Neurology of Neuromuscular and Motoneuron Diseases, University of Lübeck, Lübeck, Germany.
  • 13 Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Bochum, Germany.
  • 14 Department for Neuromuscular Diseases, Bonn University, Bonn, Germany.
  • 15 German Center for Neurodegenerative Diseases (DZNE) Site Bonn, Bonn, Germany.
  • 16 Department of Neurology, Helios Klinikum Krefeld, Krefeld, Germany.
  • 17 Department of Neurology, TUM Klinikum Rechts der Isar, München, Germany.
  • 18 German Center for Neurodegenerative Diseases (DZNE) Site Munich, Munich, Germany.
  • 19 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 20 Department of Neurology, Diako, Brüderklinikum Julia Lanz, Mannheim, Germany.
  • 21 Translational Neurodegeneration Section 'Albrecht Kossel', University Medical Center Rostock, Rostock, Germany.
  • 22 German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Germany.
  • 23 Department of Neurology, University Medical Center Rostock, Rostock, Germany.
  • 24 Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 25 Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 26 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 27 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 28 Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, Mannheim, Germany.
  • 29 Center for Rare Diseases (ZSE) Ulm, Ulm University Hospital Center for Rare Diseases, Ulm, Germany.
  • 30 Institute of Anatomy and Cell Biology, Department of Neuroanatomy, Freiburg University, Freiburg, Germany.
  • # Contributed equally.
PMID: 40781905 DOI: 10.1002/ana.70025
Abstract

Objective: Tofersen is the first effective and approved therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS [SOD1-ALS]). Following treatment with tofersen, neurofilament levels in patients' cerebrospinal fluid (CSF) and serum seem to respond earlier than clinical parameters. This evidence prompted us to hypothesize that this novel treatment could provide an opportunity to identify additional biomarkers responsive to therapy in SOD1-ALS.

Methods: We investigated a panel of 120 neural, glial, and inflammatory markers in CSF and serum samples longitudinally collected from a total of 28 SOD1-ALS patients at baseline, and after 3, 6 and 12 months of treatment with tofersen, followed by validation with conventional methodology.

Results: We identified a set of proteins, including neurofilament light chain, neurofilament heavy chain, amyloid-beta 1-40 and amyloid-beta 1-42, neuropeptide Y (NPY), and ubiquitin C-terminal hydrolase L1 (UCHL1), whose CSF levels both differed between SOD1-ALS and the control group, and were responsive to tofersen at 3 and 6 months after treatment initiation. Another group of markers, including the neuropentraxin (NPTX) family members NPTX1, NPTX2 and NPTXR, did not separate untreated SOD1-ALS from controls, but was responsive to tofersen. At 12 months on tofersen the levels of neurofilament light chain, neurofilament heavy chain, NPTX1, NPTX2, and NPTXR remained reduced compared with baseline, and correlated with the clinical response to tofersen. Consistent with increasing CSF pleocytosis and intrathecal immunoglobulin production, inflammatory markers were significantly increased after 12 months of treatment.

Interpretation: Our results highlight a complex, time-dependent differential response of CSF biomarkers to tofersen treatment, and may pave the way for developing a panel of responsive proteins to make biomarker endpoints more robust in clinical trials for SOD1-ALS and beyond. ANN NEUROL 2025;98:1318-1334.

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