Antisense Oligonucleotide Therapy 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 single-stranded DNA or RNA molecules designed to bind specifically to target messenger RNA (mRNA) sequences, thereby modulating protein expression through various mechanisms. ASO therapy represents a promising approach for neurodegenerative diseases by enabling precise genetic targeting, allele-specific silencing, and modulation of RNA splicing.
ASOs exert their effects through multiple mechanisms:
- RNase H-mediated degradation: ASOs designed with a "gapmer" structure hybridize to target mRNA, recruiting RNase H to cleave the RNA strand
- Steric blockade: ASOs bind to pre-mRNA or mRNA to block translation or splicing machinery
- RNA interference: Some ASOs can trigger the RNA-induced silencing complex (RISC)
- Splice modulation: ASOs can modulate alternative splicing by binding to splice sites or regulatory elements
| ASO Name |
Target |
Status |
Company |
| Tofersen (BIIB067) |
SOD1 |
Approved (2023) |
Biogen |
| ION363 |
FUS |
Phase 3 |
Ionis/Roche |
| BIIB078 |
C9orf72 |
Phase 1/2 |
Biogen |
| ASO Name |
Target |
Status |
Company |
| Tominersen (RG6042) |
HTT |
Phase 3 (development discontinued) |
Roche/Ionis |
| NTLA-2001 |
HTT |
Phase 1/2 |
Intellia |
| ASO Name |
Target |
Status |
Company |
| BIIB080 |
Tau |
Phase 2 |
Biogen |
| ASO-tau |
MAPT |
Preclinical |
Various |
| ASO Name |
Target |
Status |
Company |
| ASO-LRRK2 |
LRRK2 |
Preclinical |
Various |
| GBA-ASO |
GBA1 |
Preclinical |
Various |
- Intrathecal delivery: Most ASOs for CNS disorders require lumbar puncture for direct CNS delivery
- Systemic delivery: Emerging conjugated ASOs (e.g., GalNAc) enable liver and potentially CNS delivery
- AAV-vectorized: Gene therapy approaches using AAV to express shRNAs
- CSF pleocytosis: Transient inflammatory response in CSF
- Thrombocytopenia: Some ASOs affect platelet counts
- Liver toxicity: Off-target effects require monitoring
- Kidney effects: Renal clearance requires monitoring
- Blood-brain barrier: Limited CNS penetration requires invasive delivery
- Repeated dosing: ASOs require periodic administration
- Immunogenicity: Some patients develop anti-drug antibodies
- Cost: ASO therapies are extremely expensive ($100K-$500K/year)
- Conjugate delivery systems: GalNAc, CPP, and antibody-ASO conjugates
- Allele-specific ASOs: Targeting mutant alleles in dominantly inherited diseases
- Splice-switching ASOs: Modifying alternative splicing for therapeutic benefit
- Combination therapies: ASOs combined with small molecules or gene therapy
The study of Antisense Oligonucleotide Therapy 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.
- Bennett CF, et al. (2019). "Therapeutic Antisense Oligonucleotides Are Coming of Age." Annual Review of Medicine. PMID:30650068
- Torrence J, et al. (2021). "Antisense oligonucleotide therapies for neurodegenerative diseases." Neurobiology of Disease. PMID:33271245
- Miller TM, et al. (2020). "Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS." New England Journal of Medicine. PMID:32746758
- Tabrizi SJ, et al. (2019). "Targeting Huntingtin Expression in Patients with Huntington's Disease." New England Journal of Medicine. PMID:31199016
- Mummery CJ, et al. (2021). "Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease." Alzheimer's & Dementia. PMID:34028800