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Highly efficient ex-vivo correction of COL7A1 through RNP-based CRISPR/Cas9 and Homology-Directed Repair to treat recessive dystrophic epidermolysis bullosa by Camille Berthault; Sonia Gaucher; Olivier Gouin; Alain Schmitt; Mei Chen; David Woodley; Matthias Titeux; Alain Hovnanian; Araksya Izmiryan is a Medicine article available to read on EtoBox.

What is Highly efficient ex-vivo correction of COL7A1 through RNP-based CRISPR/Cas9 and Homology-Directed Repair to treat recessive dystrophic epidermolysis bullosa about?

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare and severe genetic skin disease responsible for blistering of the skin and mucosa after minor trauma. RDEB is caused by a wide variety of mutations in COL7A1 encoding C7, the major component of anchoring fibrils (AFs) which form key attachment structures for dermal-epidermal adherence. Here, we achieved highly efficient COL7A1 editing in primary RDEB keratinocytes (RDEB-K) and fibroblasts (RDEB-F) from two patients homozygous for the c.6508C>T (p.Gln2170\*) mutation through CRISPR/Cas9-mediated Homology-Directed Repair. Three gRNAs targeting the c.6508C>T mutation or harboring sequences, were delivered together with hfCas9 as a ribonucleoprotein complex (RNP). Among them, one achieved 73% cleavage activity in primary RDEB-K and RDEB-F. Then, we treated RDEB-K and RDEB-F with this specific RNP and the corresponding donor template delivered as ssODN and achieved up to 58% of genetic correction as well as C7 rescue. Finally, grafting of corrected 3D skin onto nude mice induced re-expression and normal localization of C7 as well as AFs formation at the DEJ at five and ten weeks postgrafting. With this promising non-viral appro

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Author

Camille Berthault; Sonia Gaucher; Olivier Gouin; Alain Schmitt; Mei Chen; David Woodley; Matthias Titeux; Alain Hovnanian; Araksya Izmiryan

Publisher

Elsevier BV

Published

2023

Field

Medicine (Health Sciences)