%0 Journal Article
%A Ludolph, Albert
%A Wiesenfarth, Maximilian
%T Tofersen and other antisense oligonucleotides in ALS.
%J Therapeutic advances in neurological disorders
%V 18
%@ 1756-2856
%C London [u.a.]
%I Sage
%M DZNE-2025-00233
%P 17562864251313915
%D 2025
%X The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?
%K amyotrophic lateral sclerosis (Other)
%K antisense oligonucleotides (Other)
%K superoxide dismutase (Other)
%K tofersen (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39845577
%2 pmc:PMC11752197
%R 10.1177/17562864251313915
%U https://pub.dzne.de/record/276161