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Paper comparing splice-modifying efficacy of Morpholinos and 2'-O-Me phosphorothioates

McIntosh CS, Aung-Htut MT, Fletcher S, Wilton SD. Removal of the Polyglutamine Repeat of Ataxin-3 by Redirecting pre-mRNA Processing. Int J Mol Sci. 2019;20(21):5434. doi:10.3390/ijms20215434

Excerpt from abstract:
"Here, we describe improved efficiency in the removal of the toxic polyglutamine tract of ataxin-3 in vitro using phosphorodiamidate morpholino oligomers, when compared to antisense oligonucleotides composed of 2′-O-methyl modified bases on a phosphorothioate backbone. Significant downregulation of both the expanded and non-expanded protein was induced by the morpholino antisense oligomer, with a greater proportion of ataxin-3 protein missing the polyglutamine tract. With growing concerns over toxicity associated with long-term administration of phosphorothioate oligonucleotides, the use of a phosphorodiamidate morpholino oligomer may be preferable for clinical application. These results suggest that morpholino oligomers may provide greater therapeutic benefit for the treatment of spinocerebellar ataxia type 3, without toxic effects."

Excerpt from introduction:
"Here, we describe efficient removal of the CAG containing exon 10 to produce a truncated ataxin-3
protein, lacking the polyglutamine tract, an isoform reported by Toonen et al. (2017) to be functionally
active [8]. Our study shows that by using the PMO chemistry, not only is exon 10 skipping enhanced
at the RNA level, but also significant downregulation of the protein with higher number of glutamine
repeats and an increase in production of the truncated protein is observed, when compared to the use
of the 20-Me PS AO chemistry. With robust splice switching efficiency and an established long-term
safety profile, the PMO oligomers described here are presented as lead pre-clinical candidates to treat
SCA3 patients."

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