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


Tofersen is the first effective and approved therapy for familial ALS caused by pathogenic variants in the SOD1 gene. Following treatment with tofersen, neurofilaments in patients CSF and serum display a faster response than clinical parameters, underlining their importance as a biomarker for treatment response in clinical trials. This evidence led us to hypothesize that this novel treatment might represent an opportunity to identify additional therapy-responsive biomarkers for ALS. We chose the commercial NUcleic acid Linked Immuno-Sandwich Assay (NULISA™), to investigate a predefined panel of 120 neural, glial and inflammatory markers in CSF and serum samples longitudinally collected from SOD1-ALS patients at baseline and three months after tofersen treatment. We identified a set of proteins (beyond pNfH and NfL) whose levels differed between SOD1-ALS and the matched control group and that were responsive to treatment with tofersen, including Aβ42, NPY and UCHL1. Even though our results warrant validation in larger cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in clinical trials.


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