P34 Targeted base editing restores genetic integrity in epidermolytic ichthyosis patient cells

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ID: 318372
2026
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Abstract
Abstract Introduction and aims Epidermolytic ichthyosis (EI) is an epidermal differentiation disorder caused by pathogenic variants in KRT1 and KRT10, reducing cytoskeletal stability in suprabasal keratinocytes. Many of these pathogenic variants are single-nucleotide substitutions suitable for correction by base editing, a precise CRISPR-based genome editing approach that enables targeted conversion of one nucleotide to another. We propose that genetic correction of EI-associated variants using base editors could offer a curative therapeutic strategy. Methods Our current work utilizes two-dimensional, patient-derived keratinocyte and fibroblast cultures heterozygous for the KRT10c.467G>A variant. These keratinocytes display characteristic EI phenotypes, including cytoskeletal abnormalities, reduced proliferative potential, flattened morphology from passage three, and senescence by passage five. This has prompted us to develop and validate immortalized EI keratinocyte lines for future studies. In contrast, EI fibroblasts exhibit rapid growth and long-term culture stability, making them valuable for initial optimization of editing conditions. Our initial editing has utilized lipid nanoparticle (LNP)-delivered ABE8e adenine base editor, and assessed outcomes by Sanger and amplicon sequencing. Results To date, we have performed base editing on primary EI keratinocytes using the ABE8e. We achieved 100% on-target editing efficiency, accompanied by a 23% undesired bystander edit. We are now optimizing ABE8e dosage to minimize bystander effects and are synthesizing a next-generation ABE9 variant with a narrower editing window to avoid bystander edits at this locus. Next, we will assess functional correction of the pathogenic variant through protein analysis and visualization of cytoskeletal aggregates under stress conditions. For further validation, we aim to establish a three-dimensional EI skin model and evaluate topical delivery of our editing system using LNP formulations currently being developed in our laboratory. Conclusions In conclusion, our findings demonstrate the feasibility of base editing as an efficient gene-editing strategy for EI and outline a translational pipeline that could ultimately provide a new therapeutic avenue for patients.
Reference Key
openalex_W7165624860 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors James Williamson, Nadira Ali, Jemima E. Mellerio, John A McGrath, Joanna Jackow-Malinowska
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.073
URL
https://doi.org/10.1093/bjd/ljag151.073
Keywords Keywords not found

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