Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients

Jochen H Weishaupt; Péter Körtvélyessy; Peggy Schumann; Ivan Valkadinov; Ute Weyen; Jasper Hesebeck-Brinckmann; Kanchi Weishaupt; Matthias Endres; Peter M Andersen; Martin Regensburger; Marie Dreger; Jan C Koch; Julian Conrad; Thomas Meyer

doi:10.1038/s43856-024-00573-0

Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients

Commun Med (Lond). 2024 Jul 25;4(1):150. doi: 10.1038/s43856-024-00573-0.

Authors

Jochen H Weishaupt^#¹, Péter Körtvélyessy^#^{2

3}, Peggy Schumann⁴, Ivan Valkadinov⁵, Ute Weyen⁶, Jasper Hesebeck-Brinckmann⁵, Kanchi Weishaupt⁵, Matthias Endres², Peter M Andersen⁷, Martin Regensburger^{8

9}, Marie Dreger², Jan C Koch¹⁰, Julian Conrad⁵, Thomas Meyer^{11

12}

Affiliations

¹ Division of Neurodegenerative Disorders, Neurological University Clinic Mannheim, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany. jochen.weishaupt@medma.uni-heidelberg.de.
² Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Center for ALS and other Motor Neuron Disorders, Berlin, Germany.
³ German Center for Neurodegenerative Diseases (DZNE), Research Site Magdeburg, Magdeburg, Germany.
⁴ Ambulanzpartner Soziotechnologie APST GmbH, Berlin, Germany.
⁵ Division of Neurodegenerative Disorders, Neurological University Clinic Mannheim, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
⁶ Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Department of Neurology, Center for ALS and other Motor Neuron Disorders, Bochum, Germany.
⁷ Department of Clinical Sciences, Neuroscience, Umeå University, Umeå, Sweden.
⁸ Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁹ Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany.
¹⁰ Clinic for Neurology, University Medicine Göttingen, Göttingen, Germany.
¹¹ Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Center for ALS and other Motor Neuron Disorders, Berlin, Germany. thomas.meyer@charite.de.
¹² Ambulanzpartner Soziotechnologie APST GmbH, Berlin, Germany. thomas.meyer@charite.de.

^# Contributed equally.

Abstract

Background: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1^D91A in Europe, exceeding 1% in Finno-Scandinavia.

Methods: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1^D91A allele for up to 16 months with tofersen.

Results: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1^D91A. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1^D91A. The results indicate that both mono- and bi-allelic SOD1^D91A are causally relevant targets, with a possibly reduced effect size of SOD1^D91Ahet.

Conclusions: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1^D91A patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.

Plain language summary

Amyotrophic lateral sclerosis (ALS) is a disease that can be inherited which affects nerve cells in the brain and spinal cord. Changes within a gene called SOD1 that result in a mutation named p.D91A can lead to the development of ALS. People have two copies of the SOD1 gene. It has been unclear whether the presence of only one copy of p.D91A can cause ALS. We treated ALS patients with the p.D91A variant of SOD1 with a drug called tofersen. We found that a marker of disease progression was reduced in patients with one or two copies of the p.D91A mutation. This suggests that the presence of just one p.D91A variant of SOD1 contributes to disease development. This information could be used to improve treatment decisions for people with ALS.