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Site-specific Incorporation of 2',5'-Linked Nucleic Acids Enhances Therapeutic Profile of Antisense Oligonucleotides.

ABSTRACT: Site-specific incorporation of 2'-modifications and neutral linkages in the deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined the effect of introducing 2',5'-linked RNA in the deoxynucleotide gap region on toxicity and potency of PS ASOs. Our results demonstrate that incorporation of 2',5'-linked RNA in the gap region dramatically improved hepatotoxicity profile of PS-ASOs without compromising potency and provide a novel alternate chemical approach for improving therapeutic index of ASO drugs.

SUBMITTER: Prakash TP

PROVIDER: S-EPMC8201499 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Site-specific Incorporation of 2',5'-Linked Nucleic Acids Enhances Therapeutic Profile of Antisense Oligonucleotides.

Prakash Thazha P TP Yu Jinghua J Shen Wen W De Hoyos Cheryl Li CL Berdeja Andres A Gaus Hans H Liang Xue-Hai XH Crooke Stanley T ST Seth Punit P PP

ACS medicinal chemistry letters 20210405 6

Site-specific incorporation of 2'-modifications and neutral linkages in the deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined the effect of introducing 2',5'-linked RNA in the deoxynucleotide gap region on toxicity and potency of PS ASOs. Our results demonstrate that incorporation of 2',5'-linked RNA in the gap region dramatically improved hepatotoxicity profile of PS-ASOs without compromising potency ...[more]

PMID: 34141070

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Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.

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Potent and nontoxic antisense oligonucleotides containing locked nucleic acids.

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| S-EPMC1087899 | biostudies-literature

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| S-EPMC8450106 | biostudies-literature

Sequence motifs associated with hepatotoxicity of locked nucleic acid--modified antisense oligonucleotides.

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| S-EPMC4005641 | biostudies-literature

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