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Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa

Authors
 Sung-Ah Hong  ;  Song-Ee Kim  ;  A-Young Lee  ;  Gue-Ho Hwang  ;  Jong Hoon Kim  ;  Hiroaki Iwata  ;  Soo-Chan Kim  ;  Sangsu Bae  ;  Sang Eun Lee 
Citation
 MOLECULAR THERAPY, Vol.30(8) : 2,664-2,679, 2022-08 
Journal Title
MOLECULAR THERAPY
ISSN
 1525-0016 
Issue Date
2022-08
MeSH
Animals ; Collagen Type VII* / genetics ; Collagen Type VII* / metabolism ; Epidermolysis Bullosa Dystrophica* / genetics ; Epidermolysis Bullosa Dystrophica* / pathology ; Epidermolysis Bullosa Dystrophica* / therapy ; Genes, Recessive ; Keratinocytes / metabolism ; Mice ; Mutation ; Skin / metabolism
Keywords
COL7A1 ; CRISPR ; base editing ; genome editing ; prime editing ; recessive dystrophic epidermolysis bullosa ; type VII collagen
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.
Full Text
https://www.sciencedirect.com/science/article/pii/S1525001622003653?via%3Dihub
DOI
10.1016/j.ymthe.2022.06.005
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Soo Chan(김수찬) ORCID logo https://orcid.org/0000-0002-2327-4755
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
Lee, Sang Eun(이상은) ORCID logo https://orcid.org/0000-0003-4720-9955
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/191879
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