AI Article Synopsis
- A series of novel oligonucleotides (2'-deoxy and 2'-MOE) featuring unique phosphoramidate groups were synthesized to assess their potential as splice-switching agents for spinal muscular atrophy.
- * Initial tests in patient-derived fibroblasts showed no significant difference in splice-switching efficiency between the 2'-MOE mesyl oligonucleotide and the existing treatment, nusinersen.
- * However, survival studies in neonatal mice indicated that the 2'-MOE mesyl oligonucleotide was less effective than nusinersen, likely due to issues with cellular uptake and release within cells.*
Article Abstract
A series of 2'-deoxy and novel 2'--methyl and 2'--(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 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1089/nat.2020.0860 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!