Enhancing antisense efficacy with multimers and multi-targeting oligonucleotides (MTOs) using cleavable linkers |
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Authors: | Romesh R Subramanian Mark A Wysk Kathleen M Ogilvie Abhijit Bhat Bing Kuang Thomas D Rockel Markus Weber Eugen Uhlmann Arthur M Krieg |
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Institution: | 1.RaNA Therapeutics LLC, 790 Memorial Dr., Suite 203, Cambridge, MA 02139, USA;2.Pfizer Worldwide Research and Development, 9381 Judicial Dr., Suite 200, San Diego, CA 92121, USA;3.Coley Pharmaceutical GmbH, Merowingerplatz 1a, 40225 Dusseldorf, Germany |
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Abstract: | The in vivo potency of antisense oligonucleotides (ASO) has been significantly increased by reducing their length to 8–15 nucleotides and by the incorporation of high affinity RNA binders such as 2′, 4′-bridged nucleic acids (also known as locked nucleic acid or LNA, and 2′,4′-constrained ethyl cET]). We now report the development of a novel ASO design in which such short ASO monomers to one or more targets are co-synthesized as homo- or heterodimers or multimers via phosphodiester linkers that are stable in plasma, but cleaved inside cells, releasing the active ASO monomers. Compared to current ASOs, these multimers and multi-targeting oligonucleotides (MTOs) provide increased plasma protein binding and biodistribution to liver, and increased in vivo efficacy against single or multiple targets with a single construct. In vivo, MTOs synthesized in both RNase H-activating and steric-blocking oligonucleotide designs provide ≈4–5-fold increased potency and ≈2-fold increased efficacy, suggesting broad therapeutic applications. |
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