Comparing In Vitro and In Vivo Activity of 2′-O-[2-(Methylamino)-2-oxoethyl]- and 2′-O-Methoxyethyl-Modified Antisense Oligonucleotides.

A number of 2′- O-modified antisense oligonucleotides have been reported for their potential use in oligonucleotide-based therapeutics. To date, most of the in vivo data has been generated for 2′- O-MOE (2′- O-methoxyethyl)- and 2′- O-Me (2′- O-methyl)-modified ASOs (antisense oligonucleotides). We now report the synthesis and biological activity of another 2′- O-modification, namely 2′- O-[2-(methylamino)-2-oxoethyl] (2′- O-NMA). This modification resulted in an increase in the affinity of antisense oligonucleotides to complementary RNA similar to 2′- O-MOE-modified ASOs as compared to first-generation antisense oligodeoxynucleotides. The ASO modified with 2′- O-NMA reduced expression of PTEN mRNA in vitro and in vivo in a dose-dependent manner similar to 2′- O-MOE modified ASO. Importantly, toxicity parameters such as AST, ALT, organ weights, and body weights were found to be normal similar to 2′- O-MOE ASO-treated animal models. The data generated in these experiments suggest that 2′- O-NMA is a useful modification for potential application in both antisense and other oligonucleotide-based drug discovery efforts. [ABSTRACT FROM AUTHOR]