Ionis' methyl modification could reduce ASO toxicity

Ionis thinks a single methyl modification could reduce hepatoxicity of highly potent antisense oligonucleotides, expanding the opportunities for their development.

In a paper published Monday in Nature Biotechnology, Ionis Pharmaceuticals Inc. (NASDAQ:IONS) researchers sought to reduce off-target protein binding in the three main classes of phosphorothioate antisense oligonucleotides (PS-ASOs) used for therapeutics that have high affinity for RNA targets but can be toxic. In 2′-O-methoxyethyl-modified PS-ASOs with some toxicity, as well as constrained ethyl and locked nucleic acid PS-ASOs with higher rates of toxicity, the researchers found a 2′-MOE substitution at gap position 2 decreased hepatotoxicity compared with unmodified PS-ASOs without compromising potency in mice...