Short Antisense Oligonucleotides with Novel 2′−4′ Conformationaly Restricted Nucleoside Analogues Show Improved Potency without Increased Toxicity in Animals
Punit P. Seth(Ionis Pharmaceuticals (United States)), Andrew Siwkowski(Ionis Pharmaceuticals (United States)), Charles Allerson(Ionis Pharmaceuticals (United States)), Guillermo Vasquez(Ionis Pharmaceuticals (United States)), Sam Lee(Ionis Pharmaceuticals (United States)), Thazha P. Prakash(Ionis Pharmaceuticals (United States)), Edward V. Wancewicz(Ionis Pharmaceuticals (United States)), Donna Witchell(Ionis Pharmaceuticals (United States)), Eric E. Swayze(Ionis Pharmaceuticals (United States))
Cited by 266Open Access
Abstract
The potency of second generation antisense oligonucleotides (ASOs) in animals was increased 3- to 5 -fold (ED(50) approximately 2-5 mg/kg) without producing hepatotoxicity, by reducing ASO length (20-mer to 14-mer) and by employing novel nucleoside modifications that combine structural elements of 2'-O-methoxyethyl residues and locked nucleic acid. The ability to achieve this level of potency without any formulation agents is remarkable and likely to have a significant impact on the future design of ASOs as therapeutic agents.
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