Unique O-Methoxyethyl Ribose-DNA Chimeric Oligonucleotide Induces an Atypical Melanoma Differentiation-Associated Gene 5-Dependent Induction of Type I Interferon Response□S

Antisense oligonucleotides (ASO) containing 2-O-methoxy-ethyl ribose (2-MOE) modifications have been shown to possess both excellent pharmacokinetic properties and ro-bust pharmacological activity in several animal models of human disease. 2-MOE ASOs are generally well tolerated, displaying minimal to mild proinflammatory effect at doses far exceeding therapeutic doses. Although the vast majority of 2-MOE ASOs are safe and well tolerated, a small subset of ASOs inducing acute inflammation in mice has been iden-tified. The mechanism for these findings is not clear at this point, but the effects are clearly sequence-specific. One of those ASOs, ISIS 147420, causes a severe inflammatory response atypical of this class of oligonucleotides charac-terized by induction in interferon- (IFN-) at 48 h followe