Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis
Abstract Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-12-01
|
| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.52234 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846118541124698112 |
|---|---|
| author | Daisuke Ito Kensuke Okada |
| author_facet | Daisuke Ito Kensuke Okada |
| author_sort | Daisuke Ito |
| collection | DOAJ |
| description | Abstract Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide‐based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on‐target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis. |
| format | Article |
| id | doaj-art-fa2677ed35a846d1885a8fe818c71dc7 |
| institution | Kabale University |
| issn | 2328-9503 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-fa2677ed35a846d1885a8fe818c71dc72024-12-17T16:12:21ZengWileyAnnals of Clinical and Translational Neurology2328-95032024-12-0111123054306310.1002/acn3.52234Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosisDaisuke Ito0Kensuke Okada1Memory Center Keio University School of Medicine Tokyo JapanDepartment of Neurology Keio University School of Medicine Tokyo JapanAbstract Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide‐based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on‐target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.https://doi.org/10.1002/acn3.52234 |
| spellingShingle | Daisuke Ito Kensuke Okada Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis Annals of Clinical and Translational Neurology |
| title | Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis |
| title_full | Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis |
| title_fullStr | Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis |
| title_full_unstemmed | Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis |
| title_short | Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis |
| title_sort | rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis |
| url | https://doi.org/10.1002/acn3.52234 |
| work_keys_str_mv | AT daisukeito rethinkingantisenseoligonucleotidetherapeuticsforamyotrophiclateralsclerosis AT kensukeokada rethinkingantisenseoligonucleotidetherapeuticsforamyotrophiclateralsclerosis |