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

Guanidine-bridged nucleic acid (GuNA) is a bridged nucleic acid analog with high binding affinity toward 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) and found that the dual-modification strategy could significantly improve knockdown 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 observed that GuNA-modified gapmers could evade lymphocyte-derived immune responses and kept ASO-induced toxicity in check. Taken together, the results of this study demonstrate that GuNA modification can improve the functional potential of ASOs, especially in the central nervous system.