Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 141, Issue 4, Pages 883-+Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2020.08.018
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Funding
- Wings/ProQR grants from the German Research Foundation, (Deutsche Forschungsgemeinschaft [DFG]) [NY-90 2/1, NY-90 3/2, NY 90-5/1, SFB850, SFB1160]
- EB research partnership
- DEBRA Austria
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Dystrophic epidermolysis bullosa (DEB) is a blistering skin disease caused by mutations in the gene COL7A1 encoding collagen VII, with recessive DEB (RDEB) and dominant DEB (DDEB) being the main types. The antisense oligonucleotide QR-313, targeting exon 73, shows promise for treating both RDEB and DDEB, restoring collagen VII levels in the skin.
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.
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