815632-50-9Relevant articles and documents
Comparing in vitro and in vivo activity of 2′-O-[2-(methylamino)-2- oxoethyl]- and 2′-O-methoxyethyl-modified antisense oligonucleotides
Prakash, Thazha P.,Kawasaki, Andrew M.,Wancewicz, Edward V.,Shen, Lijiang,Monia, Brett P.,Ross, Bruce S.,Bhat, Balkrishen,Manoharan, Muthiah
, p. 2766 - 2776 (2008/12/22)
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.
