antisense oligonucleotide mediated splice correction of a deep intronic mutation in opa1
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2016
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Abstract
Inherited optic neuropathies (ION) present an important cause of blindness in the European working-age population. Recently we reported the discovery of four independent families with deep intronic mutations in the main inherited optic neuropathies gene OPA1. These deep intronic mutations cause mis-splicing of the OPA1 pre-messenger-RNA transcripts by creating cryptic acceptor splice sites. As a rescue strategy we sought to prevent mis-splicing of the mutant pre-messenger-RNA by applying 2′O-methyl-antisense oligonucleotides (AONs) with a full-length phosphorothioate backbone that target the cryptic acceptor splice sites and the predicted novel branch point created by the deep intronic mutations, respectively. Transfection of patient-derived primary fibroblasts with these AONs induced correct splicing of the mutant pre-messenger-RNA in a time and concentration dependent mode of action, as detected by pyrosequencing of informative heterozygous variants. The treatment showed strong rescue effects (≃55%) using the cryptic acceptor splice sites targeting AON and moderate rescue (≃16%) using the branch point targeting AON. The highest efficacy of Splice correction could be observed 4 days after treatment however, significant effects were still seen 14 days post-transfection. Western blot analysis revealed increased amounts of OPA1 protein with maximum amounts at ≃3 days post-treatment. In summary, we provide the first mutation-specific in vitro rescue strategy for OPA1 deficiency using synthetic AONs.
| Reference Key |
bonifert2016molecularantisense
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|---|---|
| Authors | ;Tobias Bonifert;Irene Gonzalez Menendez;Florian Battke;Yvonne Theurer;Matthis Synofzik;Ludger Schöls;Bernd Wissinger |
| Journal | coordination chemistry reviews |
| Year | 2016 |
| DOI |
10.1038/mtna.2016.93
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| URL | |
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