Tofersen and other antisense oligonucleotides in ALS
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...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2025-01-01
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| Series: | Therapeutic Advances in Neurological Disorders |
| Online Access: | https://doi.org/10.1177/17562864251313915 |
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| _version_ | 1832591439311142912 |
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| author | Albert Ludolph Maximilian Wiesenfarth |
| author_facet | Albert Ludolph Maximilian Wiesenfarth |
| author_sort | Albert Ludolph |
| collection | DOAJ |
| description | 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? |
| format | Article |
| id | doaj-art-574db0154db54be7aab794820e54f413 |
| institution | Kabale University |
| issn | 1756-2864 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Therapeutic Advances in Neurological Disorders |
| spelling | doaj-art-574db0154db54be7aab794820e54f4132025-01-22T12:03:47ZengSAGE PublishingTherapeutic Advances in Neurological Disorders1756-28642025-01-011810.1177/17562864251313915Tofersen and other antisense oligonucleotides in ALSAlbert LudolphMaximilian WiesenfarthThe 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?https://doi.org/10.1177/17562864251313915 |
| spellingShingle | Albert Ludolph Maximilian Wiesenfarth Tofersen and other antisense oligonucleotides in ALS Therapeutic Advances in Neurological Disorders |
| title | Tofersen and other antisense oligonucleotides in ALS |
| title_full | Tofersen and other antisense oligonucleotides in ALS |
| title_fullStr | Tofersen and other antisense oligonucleotides in ALS |
| title_full_unstemmed | Tofersen and other antisense oligonucleotides in ALS |
| title_short | Tofersen and other antisense oligonucleotides in ALS |
| title_sort | tofersen and other antisense oligonucleotides in als |
| url | https://doi.org/10.1177/17562864251313915 |
| work_keys_str_mv | AT albertludolph tofersenandotherantisenseoligonucleotidesinals AT maximilianwiesenfarth tofersenandotherantisenseoligonucleotidesinals |