Personalized development of antisense oligonucleotides for exon skipping restores type XVII collagen expression in junctional epidermolysis bullosa

Autor: Eline Desmet, Alfred Klausegger, Jo Lambert, Verena Wally, M. Wimmer, Mireille Van Gele, Michael Ablinger, Bernadette Liemberger, Els Van Maelsaeke, Ulrich Koller, Thomas Lettner, R. Zauner, Hannah Potocki, Theresa Palmetzhofer, Stefan Hainzl, Nicole Friedl, Julia Illmer, Johann W. Bauer, Manuela Reisenberger
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Keratinocytes
0301 basic medicine
Biopsy
Junctional epidermolysis bullosa (medicine)
Autoantigens
lcsh:Chemistry
030207 dermatology & venereal diseases
Exon
0302 clinical medicine
junctional epidermolysis bullosa
Medicine and Health Sciences
Truncated protein
lcsh:QH301-705.5
Spectroscopy
integumentary system
Homozygote
Exons
General Medicine
Non-Fibrillar Collagens
Molecular therapy
Computer Science Applications
topical therapy
Antisense oligonucleotides
antisense oligonucleotides
Epidermolysis Bullosa
Junctional
molecular therapy
exon skipping
liposomes
Genotype
Cell Survival
RNA Splicing
Biology
Article
Catalysis
Cell Line
Inorganic Chemistry
03 medical and health sciences
Organ Culture Techniques
medicine
Humans
splice mutation
RNA
Messenger
Physical and Theoretical Chemistry
type XVII collagen
Gene
Molecular Biology
Organic Chemistry
Oligonucleotides
Antisense
medicine.disease
Exon skipping
Alternative Splicing
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Type XVII collagen
Mutation
Cancer research
Zdroj: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
International Journal of Molecular Sciences, Vol 22, Iss 3326, p 3326 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 7
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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