Antisense Oligonucleotides: A New Generation of Therapeutic Drugs

Antisense oligonucleotides (ASOs) are emerging as a promising new class of therapeutic drugs that can treat a wide range of diseases by selectively blocking the expression of target genes. With their precise mechanism of action and potential to treat previously untreatable conditions, ASOs represent a revolutionary approach in medicine.

What are Antisense Oligonucleotides?

Antisense oligonucleotides are short synthetic strands of nucleic acidas, usually 12–30 nucleotides in length. They work by binding through complementary base pairing to messenger RNA (mRNA) produced by target genes. This binding prevents the mRNA from being translated into the protein it codes for. By selectively reducing the levels of target proteins, ASOs can suppress disease-causing genes or restore the function of mutated genes.

Unlike traditional small molecule drugs which can have off-target effects, ASOs demonstrate highly selective inhibition as they require exact sequence complementarity to bind. This allows them to modulate the expression of a single gene implicated in disease pathogenesis, making them well-suited for conditions caused by aberrant protein levels or mutations in a single gene.

Mechanism of Action

Upon binding of an ASO to its target mRNA, a series of events unfold to prevent protein translation:

– Hybridization: The ASO binds through Watson-Crick base pairing to its complementary mRNA sequence. This binding reaction is driven by hydrogen bonding and stacking interactions between the nucleic acid bases.

– RNase H recruitment: The ASO-mRNA duplex recruits RNase H enzymes, which are endonucleases capable of cleaving the RNA strand of an RNA-DNA hybrid.

– mRNA degradation: RNase H cleavage of the target mRNA renders it susceptible to further degradation by cellular exonucleases before it can be translated to protein.

– Suppression of protein expression: With degradation of the mRNA template, ribosomes can no longer synthesize the target protein, leading to efficient suppression of its expression.

Therapeutic Applications

With their sequence-specific mechanism, ASOs show enormous potential to treat diseases across various therapeutic areas:

Neurological Disorders: Various trials are underway using ASOs to treat spinal muscular atrophy, Huntington’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease by preventing aberrant splicing or suppressing toxic proteins.

Genetic Disorders: ASOs can correct mutations by inducing targeted exon skipping of genes causing Duchenne muscular dystrophy and create functional proteins. They are also being developed for conditions like familial hypercholesterolemia and transthyretin amyloidosis.

Liver Disorders: U.S. FDA has approved several ASO drugs to lower triglyceride and cholesterol levels by targeting apolipoprotein proteins in the liver. Oligonucleotides can also treat conditions like hemophilia by increasing clotting factor levels.

Infectious Diseases: As viral replication relies on host proteins and pathways, suppressing host genes involved can help treat viral infections like hepatitis B and cytomegalovirus. ASOs are also being tested to treat COVID-19.

Regulatory Approvals and Pipeline Drugs

Due to the progress in nucleic acid chemistry and delivery technologies like conjugation to ligands or nanoparticles, ASO drugs have transitioned from research compounds to therapeutics in clinical use. Some key regulatory approvals and pipeline drugs include:

Approvals:
– Spinraza for spinal muscular atrophy (FDA, EMA)
– Waylivra for familial chylomicronemia (EMA)
– Oxlumo for hereditary transthyretin amyloidosis (FDA, EMA)

Pipeline Drugs:
– Tofersen for amyotrophic lateral sclerosis and Huntington’s disease
– Givinostat for Duchenne muscular dystrophy
– Fitusiran for hemophilia
– IONIS-TMPRSS6-L Rx for beta-thalassemia
– Volanesorsen for familial partial lipodystrophy

Challenges and Future Outlook

While ASO therapeutics have made tremendous advances, challenges remain around delivery, stability, off-target effects and immunogenicity of some chemistries. New delivery technologies and conjugation strategies are addressing these issues. The future holds promise with RNA-targeting therapies complementing small molecule and biologics to precisely modify disease-relevant pathways. As the ASO pipeline grows, these sequence-specific drugs have potential to revolutionize treatment across multiple disease areas and open new therapeutic doors. With further improvement, Antisense oligonucleotides  could emerge as a mainstream drug class shaping 21st century medicine.

Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it