October 14, 2025

Antisense oligonucleotides (ASOs) are in the clinic for a variety of indications. When administrated, ASOs are susceptible to degradation before they even reach their intended target. To overcome this challenge, chemical modifications are made to the oligonucleotide; modifications such as phosphorothioate (PS-), 2′-O-methoxyethyl- (2′-MOE), or locked-nucleic-acid (LNA). These modifications enable the ASO to escape degradation or RNase H-mediated cleavage. 

Now, a new chemical modification strategy is being investigated: circular ASO (C-ASO). The hope is that C-ASO will overcome degradation susceptibility and have stability. While linear ASOs (L-ASOs) have chemical modification of the sugar-phosphate backbone or nucleotides, C-ASOs would only be circularized to avoid degradation and have stability in serum. The chemical modifications in L-ASOs can raise concerns regarding toxicity and triggering an immune response. C-ASOs could avoid these concerns.

If C-ASOs have increased stability and are able to alleviate toxicity and immunogenity concerns, could C-ASOs be best-in-class over their L-ASO counterparts? As data emerges from the clinic, this will need to be a therapeutic modality that is watched in the RNA therapy or ASO field.

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