Back to Publications​
Back to News​
Back to The Biomarker Edge​
Publications
Annals of Neurology

Targeted proteomics upon Tofersen identifies candidate response markers for SOD1-linked amyotrophic lateral sclerosis

  • August 9, 2025
  • Alberto Catanese, et al., Department of Neurology, Ulm University
Product:
CNS Disease Panel 120, Neurology
Topic:
Disease Area:
ALS
Sample Type:
CSF
Back to Publications​
  • August 9, 2025
  • Alberto Catanese, et al., Department of Neurology, Ulm University
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
ALS
Sample Type:
CSF

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

READ Publication

Authors & Affiliations

Christina Steffke, Karthik Baskar, Maximilian Wiesenfarth, Johannes Dorst, Joachim Schuster, Florian Schöberl, Peter Reilich, Martin Regensburger, Alexander German, René Günther, Maximilian Vidovic, Susanne Petri, Jochen H. Weishaupt, Thomas Meyer, Tim Hagenacker, Julian Grosskreutz, Ute Weyen, Patrick Weydt, Thomas Haarmeier, Paul Lingor, Joachim Wolf, Andreas Hermann, Johannes Prudlo, Kornelia Günther, Antje Knehr, Zeynep Elmas, Özlem Parlak, Zeljko Uzelac, Simon Witzel, Wolfgang Philipp Ruf, Hayrettin Tumani, Albert C. Ludolph, Axel Freischmidt, Patrick Oeckl, Ritchie Ho, David Brenner, Alberto Catanese

  1. Department of Neurology, Ulm University, 89081, Ulm, Germany.
  2. Institute of Anatomy and Cell Biology, 89081, Ulm, Germany.
  3. International Graduate School, Ulm University, 89081, Ulm, Germany
  4. German Center for Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany.
  5. Department of Neurology with Friedrich Baur Institute, LMU University Hospital, LMU Munich, 80336, München, Germany.
  6. Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
  7. Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
  8. German Center for Neurodegenerative Diseases (DZNE) Site Dresden, 01307, Dresden, Germany.
  9. Department of Neurology, Hannover Medical School, 30625, Hannover, Germany.
  10. Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, 68167, Mannheim, Germany.
  11. Department of Neurology, Center for ALS and Other Motor Neuron Disorders, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, HumboldtUniversität zu Berlin, and Berlin Institute of Health, 13353, Berlin, Germany.
  12. Department of Neurology and Center for Translational Neuro and Behavioral Sciences (CTNBS), University Hospital Essen, 45127, Essen, Germany.
  13. Precision Neurology of Neuromuscular and Motoneuron Diseases, University of Lübeck, 23538, Lübeck, Germany.
  14. Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, 44789, Bochum, Germany.
  15. Department for Neurodegenerative Disorders and Gerontopsychiatry, Bonn University, 53127, Bonn, Germany.
  16. German Centre for Neurodegenerative Diseases (DZNE) Site Bonn, 53127, Bonn, Germany.
  17. Department of Neurology, Helios Klinikum Krefeld, 47805, Krefeld, Germany.
  18. Department of Neurology, Klinikum rechts der Isar der TU München, 81675, München, Germany.
  19. Department of Neurology, Diako Mannheim, Mannheim 68163, Germany.
  20. Translational Neurodegeneration Section ‘Albrecht Kossel’, University Medical Center Rostock, Rostock 18146, Germany.
  21. German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany.
  22. Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  23. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  24. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  25. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Linkedin

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Linkedin

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.