Site-specific incorporation of 5'-methyl DNA enhances the therapeutic profile of gapmer ASOs.

Autor:	Vasquez G; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Freestone GC; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Wan WB; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Low A; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., De Hoyos CL; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Yu J; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Prakash TP; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Ǿstergaard ME; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Liang XH; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Crooke ST; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Swayze EE; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Migawa MT; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Seth PP; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2021 Feb 26; Vol. 49 (4), pp. 1828-1839.
DOI:	10.1093/nar/gkab047
Abstrakt:	We recently showed that site-specific incorporation of 2'-modifications or neutral linkages in the oligo-deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined if introducing substitution at the 5'-position of deoxynucleotide monomers in the gap can also enhance therapeutic index. Introducing R- or S-configured 5'-Me DNA at positions 3 and 4 in the oligodeoxynucleotide gap enhanced the therapeutic profile of the modified ASOs suggesting a different positional preference as compared to the 2'-OMe gap modification strategy. The generality of these observations was demonstrated by evaluating R-5'-Me and R-5'-Ethyl DNA modifications in multiple ASOs targeting HDAC2, FXI and Dynamin2 mRNA in the liver. The current work adds to a growing body of evidence that small structural changes can modulate the therapeutic properties of PS ASOs and ushers a new era of chemical optimization with a focus on enhancing the therapeutic profile as opposed to nuclease stability, RNA-affinity and pharmacokinetic properties. The 5'-methyl DNA modified ASOs exhibited excellent safety and antisense activity in mice highlighting the therapeutic potential of this class of nucleic acid analogs for next generation ASO designs. (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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