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Improved Efficacy and Tolerability of Antisense Oligonucleotide with Guanidine-Bridged Nucleic Acid

Year: 2026

Type: article

Abstract: Guanidine- bridged nucleic acid (GuNA) is a bridged nucleic acid analog with high binding affinity towards complementary strands along with high nuclease resistance. GuNA has been developed to improve pharmacokinetics and safety profiles of phosphorothioate modified gapmers. Here, we evaluated antisense oligonucleotides (ASOs) modified with combination of GuNA and 2’-O-methoxyethyl (MOE) could significantly improve KD activity in vitro and in vivo. Long-term efficacy evaluation showed that intracerebroventricularly administered GuNA modified gapmers stayed active for over 24 weeks in mouse brain. Furthermore, we found that GuNA-modified gapmers could evade lymphocyte-derived immune responses and kept ASO-induced toxicity in check. Taken together, the results of this study demonstrated that GuNA modification can improve the potential of ASOs, especially in the central nervous system.

Source: Nucleic Acid Therapeutics

DOI: 10.1177/21593337261502560

Authors: Takaaki Kawanobe, Ajaya Ram Shrestha, Hideaki Tomita

Language: English

Topic: RNA Interference and Gene Delivery

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

OpenAlex ID: W7119493127

FWCI:

Cites: 37

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Related to: 10