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

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
Viggiano, Emanuela
Source :
International Journal of Molecular Sciences; Apr2021, Vol. 22 Issue 7, p3326, 1p
Publication Year :
2021

Abstract

Intermediate junctional epidermolysis bullosa caused by mutations in the COL17A1 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 COL17A1 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16616596
Volume :
22
Issue :
7
Database :
Complementary Index
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
149727603
Full Text :
https://doi.org/10.3390/ijms22073326