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Antisense oligonnucleotide treatment of COL7A1 causes non-specific splice modifications

West, K.A.ORCID: 0000-0002-7036-5334, Fletcher, S. and Wilton, S.D. (2018) Antisense oligonnucleotide treatment of COL7A1 causes non-specific splice modifications. Journal of Gene Medicine, 20 (1). e3003.

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Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disease caused by bi‐allelic mutations in the COL7A1, which results in severe blistering of the skin and mucous membranes. Current therapies treat the symptoms but not the disease. Most mutations are either small indels, point mutations that disrupt the folding of the Gly‐X‐Y repeats in the collagenous zone, or null mutations causing premature termination of the protein. Of the 118 exons in COL7A1, 107 are inframe and removal of one of these would not disrupt the mRNA reading frame. Therefore, using antisense oligonucleotides (AO) to alter splicing and remove these mutations could be a potential therapy to treat RDEB. Natural exon skipping removing a nonsense mutation in COL7A1 exon 15 and a single base‐pair insertion in exon 19 resulted in modest increases in functional COL7A1 expression and reduced disease severity in both RDEB patients. Hence, the removal of selected individual exons does not seem to affect the trimerisation of COL7A1, and therefore preserves the fibril function. However, since most COL7A1 exons are separated by small introns, targeting a single exon could impact splicing of adjacent exons. We have found that targeting COL7A1 exon 73 induced robust skipping of exon 73, but also caused removal of exon 74 and retention of intron 76. Further investigation is being carried out to understand and eliminate these non‐specific splice events. Restricting the range for transcript analysis, especially using nucleic acid based assays, could fail to detect the overall effectiveness and specificity of AOs to splice‐switch accordingly.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: John Wiley & Sons
Copyright: © 2018 John Wiley & Sons, Ltd.
Other Information: Abstract taken from the Joint 10th Australasian Gene and Cell Therapy Society (AGCTS) and Australasian Society for Stem Cell Research (ASSCR) Annual Scientific Meeting
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