Antisense oligonucleotides explained
Antisense oligonucleotides are short single strands designed to bind a specific messenger RNA and change its fate. They are one of the most clinically proven ways to drug the genome.
The antisense idea
A gene is copied into messenger RNA, which is then read to build a protein. An antisense oligonucleotide, or ASO, is designed to be complementary to a chosen messenger RNA. When the two meet inside a cell they base pair, and that binding event lets the ASO intervene before the protein is ever made.
Because the ASO is written to match one sequence, it can in principle target any gene, including the ones that make disease causing proteins that traditional small molecule drugs cannot touch.
Two ways an ASO can act
The gapmer design gets its name from its structure: a central DNA gap that RNase H needs, flanked by chemically modified wings that protect the ends and raise binding strength.
- Gapmers recruit an enzyme called RNase H, which cuts the messenger RNA wherever the ASO is bound. The message is destroyed and the protein is never made. This is how ASOs silence a harmful gene.
- Splice switching oligos do not trigger cutting. Instead they mask a splice site and redirect how the message is assembled, either restoring a functional protein or skipping a faulty section.
The chemistry that makes ASOs work
Unmodified DNA is destroyed too quickly to be a medicine. Approved ASOs combine a phosphorothioate backbone for nuclease resistance and protein binding with sugar modifications such as two prime O methyl, two prime methoxyethyl or locked nucleic acid in the wings to increase affinity for the target.
Getting the pattern of modifications right is a design problem in itself. Too little modification and the drug degrades; too much in the wrong place and RNase H can no longer act. This gapmer wing to core balance is exactly the kind of trade off Syngenis One is built to optimise.
Where ASOs are used
ASOs are already approved for spinal muscular atrophy, Duchenne muscular dystrophy, familial amyloid polyneuropathy and high cholesterol, among others. Many act in the liver or central nervous system, where delivery is most tractable, and the field is steadily expanding to new tissues and targets.
Related glossary terms
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