TY  - JOUR
AU  - Steffke, Christina
AU  - Baskar, Karthik
AU  - Bachhuber, Franziska
AU  - Wiesenfarth, Maximilian
AU  - Dorst, Johannes
AU  - Schuster, Joachim
AU  - Schöberl, Florian
AU  - Reilich, Peter
AU  - Regensburger, Martin
AU  - German, Alexander
AU  - Günther, René
AU  - Vidovic, Maximilian
AU  - Petri, Susanne
AU  - Meyer, Thomas
AU  - Hagenacker, Tim
AU  - Grosskreutz, Julian
AU  - Weyen, Ute
AU  - Weydt, Patrick
AU  - Haarmeier, Thomas
AU  - Lingor, Paul
AU  - Wolf, Joachim
AU  - Hermann, Andreas
AU  - Prudlo, Johannes
AU  - Günther, Kornelia
AU  - Knehr, Antje
AU  - Elmas, Zeynep
AU  - Uzelac, Zeljko
AU  - Witzel, Simon
AU  - Ruf, Wolfgang Philipp
AU  - Freischmidt, Axel
AU  - Ho, Ritchie
AU  - Ludolph, Albert C
AU  - Weishaupt, Jochen H
AU  - Tumani, Hayrettin
AU  - Oeckl, Patrick
AU  - Brenner, David
AU  - Catanese, Alberto
TI  - Targeted Proteomics upon Treatment with Tofersen Identifies Novel Response Markers for Superoxide Dismutase 1-Linked Amyotrophic Lateral Sclerosis.
JO  - Annals of neurology
VL  - 98
IS  - 6
SN  - 0364-5134
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DZNE-2025-01350
SP  - 1318 - 1334
PY  - 2025
AB  - 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.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.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.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.
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: cerebrospinal fluid
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: blood
KW  - Male
KW  - Female
KW  - Middle Aged
KW  - Proteomics: methods
KW  - Superoxide Dismutase-1: genetics
KW  - Biomarkers: cerebrospinal fluid
KW  - Biomarkers: blood
KW  - Aged
KW  - Adult
KW  - Neurofilament Proteins: cerebrospinal fluid
KW  - Longitudinal Studies
KW  - Superoxide Dismutase-1 (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - SOD1 protein, human (NLM Chemicals)
KW  - Neurofilament Proteins (NLM Chemicals)
KW  - neurofilament protein L (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40781905
DO  - DOI:10.1002/ana.70025
UR  - https://pub.dzne.de/record/282590
ER  -