Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

A series of 2'-deoxy and novel 2'-O-methyl and 2'-O-(2-methoxyethyl) (2'-MOE) oligonucleotides with internucleotide methanesulfonyl (mesyl, μ) or 1-butanesulfonyl (busyl, β) phosphoramidate groups has been synthesized for evaluation as potential splice-switching oligonucleotides. Evaluation of their splice-switching activity in spinal muscular atrophy patient-derived fibroblasts revealed no significant difference in splice-switching efficacy between 2'-MOE mesyl oligonucleotide and the corresponding phosphorothioate (nusinersen). Yet, a survival study with model neonatal mice has shown the antisense 2'-MOE mesyl oligonucleotide to be inferior to nusinersen at the highest dose of 40 mg/kg. A reason for their lower activity in vivo as ascertained by cellular uptake study by fluorescent confocal microscopy in HEK293 cell line could possibly be ascribed to compromised endosomal release and/or nuclear uptake of the 2'-OMe or 2'-MOE μ- and β-oligonucleotides compared to their phosphorothioate analog.

Original publication

DOI

10.1089/nat.2020.0860

Type

Journal article

Journal

Nucleic Acid Ther

Publication Date

06/2021

Volume

31

Pages

190 - 200

Keywords

2′-methoxyethyl, intracellular distribution, nusinersen, spinal muscular atrophy, splice switching, Amides, Animals, HEK293 Cells, Humans, Mice, Muscular Atrophy, Spinal, Oligonucleotides, Oligonucleotides, Antisense, Phosphoric Acids