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Advances in the application of CRISPR as a gene therapy approach for RDEB

New scientific publication from the Koller Working Group

Soon after the discovery of the gene editing tool CRISPR a few years ago, the Koller Working Group of the EB House has been putting a lot of effort in exploiting CRISPR as a therapeutic approach for EB patients. CRISPR permanently repairs the disease causing mutation in the skin cells, which as a consequence leads to the production of a healthy protein, assuring the cohesion of the skin layers. In brief, three building blocks are delivered into the cells: 1) a molecular probe that binds to the mutated site on the gene, ensuring the precision of the repair, 2) a protein, here called gene scissors, that removes the mutation by cutting the DNA, and 3) a healthy copy of the gene section that replaces the faulty one.


The first successful CRISPR repair in EB was achieved by EB House scientists in the collagen 7 gene in recessive dystrophic EB (RDEB) cells. Since then, the method has been constantly evolving, and the team has invested much research to adapt the improvements for future EB gene therapies. One of the biggest obstacles for a clinical application so far is the low efficiency and potential adverse effects due to unspecific cutting of the gene scissors in unintended sites in the genome.


In a recently published article in the journal Molecular Therapy: Nucleic Acids, the researchers compared different CRISPR approaches for collagen 7 repair in RDEB skin cells, with the aim to select the one with the highest repair efficiency and maximum precision. For this purpose, different combinations of the CRISPR building blocks were introduced into the cells. It turned out that the collagen 7 gene was most effectively and specifically corrected by the most recently developed gene scissors that cut both strands of the DNA double strand for the incorporation of the healthy gene section. This approach resulted in correct functioning of the RDEB cells without side effects, and has thus brought a clinical application of an ex vivo CRISPR gene therapy in EB patients one step closer. The next task towards this goal is to optimize the delivery of the CRISPR repair molecules into the cell.


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