DMD antisense oligonucleotide mediated exon skipping efficiency correlates with flanking intron retention time and target position within the exon
| Autor: | Remko Goossens, Nisha Verwey, Yavuz Ariyurek, Fred Schnell, Annemieke Aartsma-Rus |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | RNA Biology, Vol 20, Iss 1, Pp 693-702 (2023) |
| Druh dokumentu: | article |
| ISSN: | 1547-6286 1555-8584 15476286 |
| DOI: | 10.1080/15476286.2023.2254041 |
| Popis: | Mutations in the DMD gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic approach that allows production of a shorter but functional protein. As DMD causing mutations can affect most of the 79 exons encoding dystrophin, a wide variety of AONs are needed to treat the patient population. Design of AONs is largely guided by trial-and-error, and it is yet unclear what defines the skippability of an exon. Here, we use a library of phosphorodiamidate morpholino oligomer (PMOs) AONs of similar physical properties to test the skippability of a large number of DMD exons. The DMD transcript is non-sequentially spliced, meaning that certain introns are retained longer in the transcript than downstream introns. We tested whether the relative intron retention time has a significant effect on AON efficiency, and found that targeting an out-of-frame exon flanked at its 5’-end by an intron that is retained in the transcript longer (‘slow’ intron) leads to overall higher exon skipping efficiency than when the 5’-end flanking intron is ‘fast’. Regardless of splicing speed of flanking introns, we find that positioning an AON closer to the 5’-end of the target exon leads to higher exon skipping efficiency opposed to targeting an exons 3’-end. The data enclosed herein can be of use to guide future target selection and preferential AON binding sites for both DMD and other disease amenable by exon skipping therapies. |
| Databáze: | Directory of Open Access Journals |
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