Antisense Oligonucleotides: A Promising New Class of Drugs
Mechanism of Action of Antisense Oligonucleotides
Antisense oligonucleotides, also known as ASOs, work through a mechanism called
steric blocking. They are designed to bind through complementary base pairing
to messenger RNA (mRNA) produced from a gene, thereby preventing the mRNA from
translating into the associated disease-causing protein. By reducing the levels
of target proteins, ASOs can suppress or correct the root causes of genetic
disorders and some acquired diseases.
ASOs
are short strings of nucleotides that are engineered to bind tightly and
specifically to their target mRNA sequences. Once bound, the ASO-mRNA duplex
triggers the recruitment of RNase H, an enzyme that degrades the mRNA strand of
the duplex, preventing translation and effectively reducing protein production.
This mechanism of steric blocking allows ASOs to inhibit the expression of a
protein from a gene without directly modifying DNA.
Precision targeting: ASOs have exquisite precision as they can target single
mRNA transcripts for degradation, allowing clinicians to selectively modulate
individual disease-causing proteins.
Oral bioavailability: Many ASOs are designed to be orally bioavailable through
modifications that help them bypass degradation by enzymes in the
gastrointestinal tract and assist uptake into tissues. This oral dosing
provides significant advantages over other injectable therapies.
Durable target lowering: After a single dose, many ASOs can maintain levels of
target proteins lowered for months due to their ability to repeatedly trigger
mRNA degradation over time in tissues.
Protein-independent mechanism: Unlike other therapeutic modalities like gene
therapy that modify DNA or gene editing which relies on DNA repair machinery,
ASOs work directly through an RNA interference mechanism independent of protein
function. This broader mechanism makes them applicable against a wide range of
targets.
Commercial & Clinical Progress
Several ASO drugs have already gained regulatory approval and are commercial
successes. Spinraza, the first drug approved for spinal muscular atrophy,
generated over $1.7 billion in annual sales. Waylivra, which treats familial
chylomicronemia syndrome, was approved in the EU in 2020.
In clinical trials, investigational ASOs are demonstrating significant promise
across a range of disease areas:
Cardiometabolic: ASOs targeting apolipoprotein(a) and angiopoprotein-like 3
have both met primary endpoints in Phase 2 trials for cardiovascular disease.
Neurodegeneration: Multiple programs are in testing for amyotrophic lateral
sclerosis, Alzheimer's disease, Parkinson's disease and other neurodegenerative
conditions.
Hepatic disorders: Programs targeting acute hepatic porphyria and alpha-1
antitrypsin deficiency are in late-stage studies.
Ophthalmology: ASOs for retinal diseases like AMD have also shown efficacy in
initial human studies.
Genetic modifiers: Modulating DNA repair genes with ASOs aims to enhance the
activity of other cancer therapies.
Widespread Applicability & Pipeline Growth
The success of approved ASO drugs and ongoing clinical progress have validated
this modality's ability to target previously undruggable genes linked to human
diseases. As target validation and delivery techniques continue improving, many
more programs are projected to enter development. Genetic diseases, various
cancers and more are being targeted.
Several big pharmaceutical companies have also significantly expanded their ASO
research pipelines in recent years based on these promising results. With
orphan drug designations and premium pricing, newly approved ASO treatments
represent valuable new product families. The increased focus on RNA-targeting
modalities is a testament to ASOs' clinical and commercial potential as a major
new class of precision biologic drugs.
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Oligonucleotides
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