Base & Prime Editing for RDEB

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Current Projects, Gene Editing, Quality of Life Change, Whole Body Treatment
About This Project

Base and Prime Editing Strategies for Recessive Dystrophic Epidermolysis Bullosa

Lay summary

Individuals with recessive dystrophic epidermolysis bullosa (RDEB) suffer from widespread blistering of external and internal skin, along with complications such as poor wound healing, narrowing of the oesophagus (food pipe) due to scarring, corneal erosions (damage to the outer surface of the eye), fusion of fingers and toes, and the development of skin cancer. The condition is caused by mutations in COL7A1, the gene encoding type VII protein, and there is currently no specific treatment.

The goal of our research is to provide a treatment that will improve the quality of life of patients by preventing and/or treating skin complications of RDEB. The project aims to develop a strategy that could be used to treat a significant subset of RDEB patients carrying selected mutations.

The project will investigate the feasibility of base and prime editing strategies in primary RDEB cells in vitro and ex vivo, but also in vivo using new delivery methods such as lipid nanoparticles or virus-like particles which are devoid of viral genetic material. The project will target 10 COL7A1 recurrent mutations which are present in 13.5% of the RDEB patient population.

Scientific Summary

This project aims to develop base and prime editing strategies to correct recurrent COL7A1 mutations in primary keratinocytes, fibroblasts and iPSCs from RDEB patients.

We will design the most efficient gRNAs and pegRNAs in combination with base and/or prime editors (BEs; PEs) which will be delivered into cultured RDEB cells using either mRNA nucleofection, virus like particles (VLPs) or lipid nanoparticles (LNPs).

Subsequently, LNPs or VLPs will be delivered by intradermal or intravenous injections into nude mice grafted with RDEB skin equivalents. Restoration of type VII collagen function will first be assessed in skin organoids, then in skin equivalents grafted onto nude mice.

Project update – April 2026

In this project, we are exploring a new therapeutic approach called base editing, which offer major advantages compared with conventional gene therapy strategies. Unlike CRISPR-Cas9 systems, they enable direct and permanent conversion of the mutated base into the corrected base through their deaminase activity, without cutting the DNA, which may make it safer and more efficient.

We are focusing on the correction of different disease-causing mutations with high recurrence. Targeting recurrent pathogenic variants maximizes the number of eligible patients and increases the clinical impact of this approach. Our goal is to correct these mutations in patient-derived skin cells in the laboratory and to determine whether this restores the production of type VII collagen.

Our results are very promising. Preliminary results showed up to 90% of correction for two different pathogenic variants frequent in European populations. This genetic correction also led to the restoration of type VII collagen production, responsible for dermal-epidermal adherence and in skin integrity.

We are now testing these corrected cells in laboratory-grown skin models to evaluate whether normal skin function can be restored. In parallel, we are developing delivery methods, such as lipid nanoparticles or virus like particles, to efficiently transport the gene-editing tools into cells, an essential step toward future clinical applications.

Researchers
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