Antisense Oligonucleotides For Neurodegeneration is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Antisense oligonucleotides (ASOs) are short, synthetic single-stranded DNA or RNA molecules designed to bind to specific messenger RNA (mRNA) sequences, thereby modulating gene expression. ASOs represent a transformative therapeutic modality for neurodegenerative diseases, enabling targeted reduction of toxic protein aggregates, correction of aberrant splicing, and allele-specific silencing of disease-causing mutations. Several ASOs have now received FDA approval for neurological disorders, with numerous candidates in clinical development for Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). [1]
ASOs employ several mechanisms to achieve therapeutic effects: [2]
| Mechanism | Description | [3]
|-----------|-------------| [4]
| RNase H-Mediated Degradation | ASO-RNA hybrid recruits RNase H to cleave RNA | [5]
| Steric Blockade | Blocks translation initiation or splicing machinery | [6]
| RNA Silencing | Uses RNA interference pathways | [7]
| Splice Modulation | Corrects aberrant splicing patterns |
| Allele-Specific Targeting | Targets mutant allele while sparing wild-type |
| Drug | Target | Indication | Phase | Mechanism |
|---|---|---|---|---|
| BIIB080 | Tau (MAPT) | AD | I/II | RNase H |
| ASO-GC | GC (MIR137) | PD/AD | Preclinical | Splice modulation |
| ASO-α-syn | SNCA | PD | Preclinical | RNase H |
| C9orf72 | C9orf72 | ALS/FTD | I/II | Target repeat RNA |
| ATXN2-ASO | ATXN2 | ALS | Preclinical | RNase H |
| Trial | Drug | Target | Phase | Status | Indication |
|---|---|---|---|---|---|
| NCT03761849 | Tominersen | HTT | III | Discontinued | Huntington's disease |
| NCT02644599 | Tofersen | SOD1 | III | Approved | SOD1-ALS |
| NCT03186118 | Nusinersen | SMN2 | III | Approved | SMA |
| NCT04784160 | BIIB080 | Tau | I/II | Recruiting | Alzheimer's disease |
| NCT04297605 | IONIS-C9Rx | C9orf72 | I/II | Completed | ALS/FTD |
Current research focuses on:
The study of Antisense Oligonucleotides For Neurodegeneration 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.
FDA. Qalsody (tofersen) injection approval letter. 2023. 2023. ↩︎
Tabrizi SJ, et al. Targeting huntingtin protein in Huntington's disease. 2019. ↩︎
Miller T, et al. Phase 1-2 trial of tofersen for SOD1 ALS. 2020. ↩︎
Mercuri E, et al. Nusinersen in spinal muscular atrophy. 2018. ↩︎
Mummery CJ, et al. BIIB080 (IONIS-MAPTRx) in mild Alzheimer's disease. 2023. ↩︎
Hu J, et al. Allele-specific silencing of mutant huntingtin. 2020. ↩︎
Kordas G, et al. Antisense oligonucleotides for Parkinson's disease. 2022. ↩︎