Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa

Intermediate junctional epidermolysis bullosa caused by mutations in the gene is characterized by the frequent development of blisters and erosions on the skin and mucous membranes. The rarity of the disease and the heterogeneity of the underlying mutations renders therapy developments challenging....

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 22; no. 7; p. 3326
Main Authors:	Ablinger, Michael, Lettner, Thomas, Friedl, Nicole, Potocki, Hannah, Palmetzhofer, Theresa, Koller, Ulrich, Illmer, Julia, Liemberger, Bernadette, Hainzl, Stefan, Klausegger, Alfred, Reisenberger, Manuela, Lambert, Jo, Van Gele, Mireille, Desmet, Eline, Van Maelsaeke, Els, Wimmer, Monika, Zauner, Roland, Bauer, Johann W, Wally, Verena
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 24-03-2021 MDPI
Subjects:	Alternative Splicing Antisense oligonucleotides Autoantigens - metabolism Binding sites Biopsy Blistering Blisters Cell Line Cell Survival Collagen Collagen Type XVII Customization Epidermolysis bullosa Epidermolysis Bullosa, Junctional - genetics Epidermolysis Bullosa, Junctional - metabolism Epidermolysis Bullosa, Junctional - therapy Exon skipping Exons Genes Genotype Genotypes Heterogeneity Homozygote Humans Junctional epidermolysis bullosa Keratinocytes - cytology Liposomes - chemistry Microscopy molecular therapy mRNA mRNA processing Mutation Non-Fibrillar Collagens - metabolism Oligonucleotides, Antisense - genetics Organ Culture Techniques Patients Post-transcription Proteins RNA Splicing RNA, Messenger - metabolism Skin splice mutation type XVII collagen junctional epidermolysis bullosa splice mutation molecular therapy exon skipping liposomes antisense oligonucleotides type XVII collagen topical therapy
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Summary:	Intermediate junctional epidermolysis bullosa caused by mutations in the gene is characterized by the frequent development of blisters and erosions on the skin and mucous membranes. The rarity of the disease and the heterogeneity of the underlying mutations renders therapy developments challenging. However, the high number of short in-frame exons facilitates the use of antisense oligonucleotides (AON) to restore collagen 17 (C17) expression by inducing exon skipping. In a personalized approach, we designed and tested three AONs in combination with a cationic liposomal carrier for their ability to induce skipping of exon 7 in 2D culture and in 3D skin equivalents. We show that AON-induced exon skipping excludes the targeted exon from pre-mRNA processing, which restores the reading frame, leading to the expression of a slightly truncated protein. Furthermore, the expression and correct deposition of C17 at the dermal-epidermal junction indicates its functionality. Thus, we assume AON-mediated exon skipping to be a promising tool for the treatment of junctional epidermolysis bullosa, particularly applicable in a personalized manner for rare genotypes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms22073326