What are ASOs?
Antisense oligonucleotides (ASOs) are short, synthetic nucleotides that will match target RNA molecules via Watson-Crick base pairing. This binds allows ASOs to regulate gene expression either by causing the untranslation of mRNA or its destruction. The specificity and versatility of ASOs have changed gene therapy, and now they are used to treat a wide range of genetic and acquired conditions.
What is the mechanism of action of ASOs?
The primary mechanism of ASOs involves sequence-specific hybridization to complementary RNA molecules. Upon binding, ASOs can:
- Inhibit Translation: Sterically block the ribosome's access to mRNA.
- Induce Degradation: Recruit RNase H enzymes to degrade the RNA strand within the RNA-DNA duplex.
- Modulate Splicing: Alter pre-mRNA splicing patterns to correct aberrant protein expression.
Figure 1. Mechanism of action of ASOs[1].
What are the therapeutic areas of ASOs?
ASOs have shown immense potential in treating diseases by targeting specific genetic sequences. Notable applications include:
Cancer Therapy
ASOs are employed to suppress oncogene expression, such as MDM2 and Pim-2, thereby inhibiting tumor cell proliferation and inducing apoptosis.
Neurological Disorders
- Spinal Muscular Atrophy (SMA): Nusinersen (Spinraza), the first FDA-approved ASO, enhances SMN protein levels by modulating SMN2 splicing.
- Amyotrophic Lateral Sclerosis (ALS): Tofersen targets the SOD1 gene, while QRL-201 restores stathmin-2 levels, addressing neurodegenerative pathways.
- Huntington's Disease: ASOs such as tominersen aim to reduce mutant HTT protein expression, though clinical outcomes remain variable.
Rare Genetic Diseases
Inotersen (Tegsedi) has been approved to treat hereditary transthyretin-mediated amyloidosis (hATTR) by reducing transthyretin protein levels.
Other Neurodegenerative Diseases
ASO treatments have also been shown to slow or halt neurodegeneration in Parkinson's disease, spinal cerebellar ataxia, and tauopathies through inhibition of genes (such as HTT, LRRK2, SNCA, and ATXN genes) and suppression of aberrant proteins.
Chemical Modification of ASOs
The clinical success of ASOs depends on their stability and bioavailability. Alfa Chemistry provides a wide range of modified ASOs to address these challenges. Key modification strategies include:
A. Phosphorothioate (PS) Modifications
Replace oxygen with sulfur in the phosphate backbone.
Improve nuclease resistance, cellular uptake, and systemic bioavailability.
B. 2'-O-Methyl (2'-OMe) Modifications
Increase resistance to enzymatic degradation.
Minimize off-target effects and toxicity, especially when strategically placed at gap sites.
C. Locked Nucleic Acid (LNA) Modifications
Introduce a bridge structure locking the ribose conformation.
Enhance binding affinity and thermal stability while reducing non-specific interactions.
Figure 2. Chemical modifications of the sugar-phosphate backbone of ASOs[2].
ASOs, for all their potential, are hampered by poor in vivo specificity and off-target effects. Alfa Chemistry's leading research efforts are dedicated to achieving better ASO design using novel chemical modifications and delivery mechanisms for decreased toxicity and greater therapeutic efficacy.
The acceleration of ASO technologies reflects the potential for new therapeutic opportunities in unmet medical needs across therapeutic domains. Alfa Chemistry is a leader in ASO innovations, providing high-quality synthesis and modification services for research and clinical applications. Through advanced technologies, we will promote ASO-based treatments that allow researchers to create new potential in precision medicine.
References
- Karaki S., et al. Antisense Oligonucleotides, A Novel Developing Targeting Therapy. Antisense Therapy. 2019.
- Serres-Bérard T De., et al. Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1. Antisense Therapy. 2022. 23(21), 13359.
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