QR-313, an Antisense Oligonucleotide, Shows Therapeutic Efficacy for Treatment of Dominant and Recessive Dystrophic Epidermolysis Bullosa: A Preclinical Study.

Abstract

Dystrophic epidermolysis bullosa (DEB) is a blistering skin disease caused by mutations in the gene COL7A1 encoding collagen VII. DEB can be inherited as recessive DEB (RDEB) or dominant DEB (DDEB) and is associated with a high wound burden. Perpetual cycles of wounding and healing drive fibrosis in DDEB and RDEB, as well as the formation of a tumor-permissive microenvironment. Prolonging wound-free episodes by improving the quality of wound healing would therefore confer substantial benefit for individuals with DEB. The collagenous domain of collagen VII is encoded by 82 in-frame exons, which makes splice-modulation therapies attractive for DEB. Indeed, antisense oligonucleotide-based exon skipping has shown promise for RDEB. However, the suitability of antisense oligonucleotides for treatment of DDEB remains unexplored. Here, we developed QR-313, a clinically applicable, potent antisense oligonucleotide specifically targeting exon 73. We show the feasibility of topical delivery of QR-313 in a carbomer-composed gel for treatment of wounds to restore collagen VII abundance in human RDEB skin. Our data reveal that QR-313 also shows direct benefit for DDEB caused by exon 73 mutations. Thus, the same topically applied therapeutic could be used to improve the wound healing quality in RDEB and DDEB.

• Authors: Olivier Bornert, Marieke Hogervorst, Pauline Nauroy, Johannes Bischof, Jim Swildens, Ioannis Athanasiou, Sara F Tufa, Douglas R Keene, Dimitra Kiritsi, Stefan Hainzl, Eva M Murauer, M Peter Marinkovich, Gerard Platenburg, Ingrid Hausser, Verena Wally, Tita Ritsema, Ulrich Koller, Elisabeth M Haisma, Alexander Nyström
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 4 Pg. 883-893.e6 (04 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 32946877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• COL7A1 protein, human
• Col7a1 protein, mouse
• Collagen Type VII
• Oligonucleotides, Antisense

Topics

• Animals
• Biopsy
• Cell Line
• Collagen Type VII (genetics)
• Disease Models, Animal
• Epidermolysis Bullosa Dystrophica (genetics, pathology, therapy)
• Exons (genetics)
• Fibroblasts
• Fibrosis
• Genetic Therapy (methods)
• Humans
• Keratinocytes
• Mice
• Mice, Transgenic
• Mutation
• Oligonucleotides, Antisense (administration & dosage, genetics)
• Primary Cell Culture
• Skin (drug effects)
• Wound Healing (genetics)