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- W4366190444 abstract "Base editing, the introduction of a single base correction in genomic DNA, has the potential to treat genetic skin diseases such as dystrophic epidermolysis bullosa (DEB), which is characterized by pathogenic variants in COL7A1 and type VII collagen (C7) deficiency. Hitherto, base editing has been harnessed to correct disease-causing variants but reproducibility to ensure efficient and safe gene modification needs optimization. Adenine base editors (ABEs) convert A-T base pairs to G-C base pairs without requiring double-stranded DNA breaks or donor DNA templates. Of note, C>T and G>A mutations account for ∼52% of DEB pathogenic variants, thus making ABE an ideal tool for COL7A1 correction. Here, we employ ABE8e, a new variant of ABE, for COL7A1 correction in primary DEB patients fibroblasts harboring: 1) heterozygous c.5047C>T (p.Arg1683*) in exon 54; 2) homozygous c.4448G>A (p.Gly1483Asp) in exon 42; 3) dominant c.6100G>A (p.Gly2034Asp) in exon 73 mutation, to compare efficiency and assess reproducibility of correction. Delivery of ABE8e mRNA with synthetic gRNA using lipofectamine to DEB patient fibroblasts resulted in 100% correction using a 1:2 ratio of sgRNA to ABE8e for all 3 pathogenic alleles; C7 protein was also restored in western blots. ABE8e correction yielded homogenous populations of gene corrected primary fibroblasts with remarkable efficiency, allowing for large scale correction with no need for elimination of non-edited cells. Preliminary safety studies did not detect off-target editing in treated fibroblasts. Taken together, we have established a highly reproducible pipeline for COL7A1 correction using base editor ABE8e in primary fibroblasts with 3 different pathogenic variants, work which lays a foundation for future progression to patients." @default.
- W4366190444 created "2023-04-19" @default.
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- W4366190444 date "2023-05-01" @default.
- W4366190444 modified "2023-09-28" @default.
- W4366190444 title "884 Reproducible correction of COL7A1 nonsense variants with ABE8e adenine base editor" @default.
- W4366190444 doi "https://doi.org/10.1016/j.jid.2023.03.894" @default.
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