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Improved CRISPR correction of a collagen 17 gene mutation in junctional EB cells

New scientific publication by the Koller working group from the EB house

Gene therapy strategies are the most advanced therapeutic approaches for EB. The gene replacement therapy, in which a healthy gene is inserted into skin cells, has been applied in patients with recessive dystrophic EB (RDEB) and junctional EB (JEB) with mutations in the laminin gene. A first clinical trial of this therapy has already been conducted in a patient with collagen 17-associated JEB. Nevertheless, the development of gene therapies for this type of has been slow. Therefore, the Koller working group from the EB house has set itself the goal of establishing a specially tailored gene therapy for this group of patients using the CRISPR gene scissors. Unlike gene replacement therapy, CRISPR permanently corrects the gene mutation in the cells. As a result, the cells own gene can produce a healthy protein. Currently, low gene repair efficiencies hinder its application on patients. However, the EB house researchers consistently improve the efficiency and safety of this gene therapy in order to advance its clinical application. A few months ago, they published the promising results of a CRISPR gene therapy approach in JEB skin cells carrying a mutation in the collagen 17 gene. In this study, the gene scissors were used to slightly alter the gene composition, resulting in the production of a functional collagen 17 protein in the cells. In a recent study, they tested a more advanced approach in which the mutated gene DNA is not only altered, but accurately replaced with a healthy copy. The result is a traceless gene correction. In addition, the known risk of the gene scissors to accidentally cutting other parts of the genome is reduced with this method, as the inserted CRISPR tools are degraded in the cells after they have done their work.

The successful correction of JEB cells resulted in the presence of normal amounts of collagen 17 between the skin layers in a 3D skin model. Analyses have shown that up to 60 % of all treated cells produced an intact collagen 17 protein, and thus represents the most successful CRISPR repair in a JEB gene to date. This repair efficiency may be sufficient for a therapeutic benefit, as observations suggest that the corrected cells may have a higher survival rate in the skin than cells lacking collagen 17 protein. It remains to be verified whether the CRISPR corrected JEB skin cells actually outcompete the non-corrected skin cells over time after administration into the skin.



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