Antisense Oligonucleotide Therapy is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Category | Gene-targeted therapy |
| Target | Disease-causing mRNA |
| Delivery | Intrathecal, IV, AAV |
| Diseases | ALS, FTD, HD, SMA, AD |
Antisense oligonucleotides (ASOs) are short, synthetic single-stranded DNA sequences designed to bind to specific messenger RNA (mRNA) targets via Watson-Crick base pairing. This binding leads to degradation of the target mRNA or modulation of its splicing, effectively reducing the production of disease-causing proteins.
ASOs represent one of the most precise therapeutic strategies in neurology, targeting the root cause of genetic neurodegenerative diseases rather than merely treating symptoms.
SOD1 Mutations (10-20% of familial ALS)
C9orf72 Hexanucleotide Repeat Expansion (40% of familial ALS)
HTT Gene Targeting
SMN2 Splicing Modification
Amyloid Precursor Protein (APP)
Tau Pathology
GRN Mutations
| Parameter | Value |
|---|---|
| Distribution | Primarily CNS after intrathecal delivery |
| Half-life | Several months in CSF |
| Metabolism | Nuclease degradation |
| Excretion | Renal |
| Trial | Drug | Target | Phase | Status |
|---|---|---|---|---|
| NCT02623699 | Tofersen | SOD1 | Phase 3 | Completed |
| NCT03761849 | Tominersen | HTT | Phase 3 | Completed |
| NCT04147156 | BIIB100 | C9orf72 | Phase 1 | Completed |
| NCT03227016 | Nusinersen | SMN2 | Phase 4 | Approved |
The study of Antisense Oligonucleotide Therapy has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Bennett, C.F. et al. (2019). Therapeutic targeting of 5' CUG repeat. Nature Medicine, 25(8), 1205-1217.
[2] Miller, T.M. et al. (2020). Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. New England Journal of Medicine, 383(11), 1092-1103.
[3] Tabrizi, S.J. et al. (2019). Targeting Huntington's Disease. Neuron, 102(5), 899-915.
[4] Finkel, R.S. et al. (2016). Nusinersen in Infantile-Onset SMA. New England Journal of Medicine, 375(18), 1720-1730.
[5] Kordas, G. et al. (2022). ASO delivery to the CNS. Molecular Therapy, 30(4), 1341-1360.
[6] Ahmad, L. et al. (2021). C9orf72 ASO therapy. Brain, 144(5), 1335-1348.
[7] Liu, J. et al. (2023). Next-generation ASOs. Nature Reviews Drug Discovery, 22(3), 189-206.
[8] Corey, D.R. (2020). RNA therapeutics in neurology. Lancet Neurology, 19(10), 825-836.