Figure 2.

Mechanism of Action of Gapmer ASOs

(A) Expression of an example target gene from transcription through translation of a wild-type or toxic protein. (B) Gapmer ASO with the typical structure of modified chemistry in the wings to protect the ends from nucleases and an internal stretch of DNA that leads to the formation of the RNA-DNA hybrid when bound to the target transcript. In this example, the gapmer ASO binds to an exon in the pre-mRNA and mRNA and recruits RNase H that recognizes the RNA/DNA hybrid and cleaves the RNA. The cleavage triggers RNA degradation, leading to reduction of wild-type or toxic protein levels. Gapmer ASOs can be designed to target other transcript regions, e.g., introns. Even though RNase H is more abundant in the nucleus, RNase H-mediated cleavage of RNA-DNA hybrids can also occur in the cytoplasm.