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

International Journal of Molecular Sciences

Eline Desmet¹  Mireille Van Gele¹  Els Van Maelsaeke¹  Jo Lambert¹  Bernadette Liemberger²  JohannW. Bauer²  Julia Illmer²  Thomas Lettner²  Alfred Klausegger²  Verena Wally²  Roland Zauner²  Ulrich Koller²  Stefan Hainzl²  Manuela Reisenberger²  Monika Wimmer²  Nicole Friedl²  Michael Ablinger²  Theresa Palmetzhofer²  Hannah Potocki² 

[1] Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium;Research Program for Molecular Therapy of Genodermatoses, EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria;

关键词: molecular therapy;    junctional epidermolysis bullosa;    type XVII collagen;    splice mutation;    antisense oligonucleotides;    exon skipping;   

DOI  :  10.3390/ijms22073326

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown