gapmers

Gapmers are a class of antisense oligonucleotides designed to recruit RNase H and degrade target RNA. They consist of a central DNA-like gap flanked by chemically modified nucleotides, commonly with a phosphorothioate backbone. This design enables strong binding to complementary RNA while enabling RNase H1 to recognize the DNA-RNA hybrid and cleave the RNA strand, reducing expression of the target gene.

In typical gapmer designs, the central gap is about 8–12 nucleotides long and is surrounded by modified wings (for example, 2'-O-methyl, 2'-MOE, or locked nucleic acids) that increase affinity and resistance to nucleases. The modified wings also help minimize unwanted immune activation. The phosphorothioate backbone further enhances nuclease resistance and pharmacokinetic properties, aiding stability in biological fluids.

Gapmers are used to downregulate disease-associated transcripts in a range of conditions, including genetic, metabolic, and neurodegenerative diseases. They can be delivered systemically or locally, with tissue distribution influenced by backbone chemistry and any conjugates or delivery strategies employed. Unlike steric-blocking antisense oligos that modulate splicing or translation without recruiting RNase H, gapmers rely on RNase H to degrade the RNA component of the duplex.

Safety and efficacy considerations include potential off-target effects, immune stimulation, and organ toxicity at higher doses, underscoring the importance of precise sequence design and optimized delivery. The gapmer concept emerged in the 1990s and has become a foundational approach in antisense therapeutics, supported by advances in chemical modification and delivery technologies.