A less common CRISPR-mediated repair strategy shows promise for both, RDEB and DDEB patients

New scientific publication from the Working Group Koller

The gene editing tool CRISPR has reached widespread use for the development of gene therapy approaches in EB. A new study published by EB House researchers in the renowned Journal of Investigative Dermatology, demonstrates the potential of a yet less common CRISPR-induced repair strategy capable to treat both, recessive (RDEB) and dominant dystrophic EB (DDEB).
 
Every CRISPR strategy introduces a gene scissor into the cells that cuts the gene DNA at a specific location near the mutation. Scientists can exploit different pathways for the subsequent repair, depending on which therapeutic result should be achieved. Using the so far most applied strategy, a healthy gene piece is co-delivered into the cells to replace the mutated one. This method has been in the spotlight for therapy development, even though it is less efficient than the less applied strategy named “end-joining”. The main reason is that end-joining repairs the DNA randomly, which can negatively alter the gene function. However, similarly as recently published, EB House researchers found a way to make this strategy applicable for the precise repair of EB skin cells.

In this study, the researchers used CRISPR-mediated end-joining for two different goals:  1. To repair the faulty gene, so that a functional protein can be produced as a result. This is important in recessive EB forms, where the protein is missing. 2. To inactivate the gene, so that it no longer can produce a faulty protein causing the disease in dominant EB forms.

Both approaches have been tested in skin cells in the laboratory. The EB House researchers demonstrated for the first time that the CRISPR-induced end-joining strategy can specifically repair the mutated gene in RDEB skin cells, which led to a more than 70 % increase of the healthy collagen 7 protein. Its potential future applicability for DDEB patients was proven by a 40 % reduction of collagen 7 protein in treated skin cells.

This study suggests that CRISPR-mediated end-joining is applicable for the repair of both, RDEB and DDEB, showing some advantages over the previously used strategies, such as a higher and faster repair capacity. After this first success, more experiments need to be done to fully explore its suitability for a clinical application.

 

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