Efficient correction of collagen 7 mutations in DEB skin cells using the trans-splicing method
New scientific publication from the EB house
Since the opening of the EB house, the scientists aimed to develop causal therapies for EB. The primary goal is to offer patients the most effective and at the same time safest therapy approach. For a long time, the trans-splicing technology was considered the most promising method to correct disease-causing mutations in EB skin cells. Since the discovery of the CRISPR gene editing technology, the focus has been on this new development. However, each method has advantages and disadvantages, and every patient has different needs. Thus, the therapeutic approach needs to be tailored to the individual.
The trans-splicing therapy has been studied particularly well for dystrophic EB (DEB), in which mutations in the collagen 7 gene affect the production of a fully functional collagen 7 protein in the skin. Trans-splicing is applicable to both recessive DEB (RDEB) patients, characterized by severe blistering, and dominant DEB (DDEB) patients, with milder localized blistering, for whom therapy development has not been a focus for a long time.
In an earlier approach, the researchers developed a repair molecule (RTM), which is introduced into the skin cells of DEB patients in the lab, where it replaces the faulty part of the gene transcript with the correct one in a targeted manner. As a result, a functional protein is produced from the corrected transcript, which ensures the cohesion of the skin layers. This RTM can be used for treatment of all patients harbouring mutations in the lower portion of the collagen 7 gene. In a recent publication the researchers also demonstrated the successful correction of the front portion using a second RTM. In this study, they introduced the RTM into RDEB skin cells in a petri dish using a viral delivery system. As a result, a functional collagen 7 protein was produced, which was deposited between the layers of the skin grown from the corrected cells.
For a clinical application of trans-splicing, the ex vivo skin grafting protocol already used in gene therapy trials in EB patients, can be adapted. For this purpose, the RTM is introduced into skin stem cells. A thin skin layer is then grown from the corrected cells, which is transplanted onto wounds. Another possibility is the direct delivery of the RTM into the skin (in vivo), for example by means of injections or by applying a topical cream or a spray. However, no permanent correction is achieved with this method, and it therefore must be administered repeatedly. Before going to clinics, safety tests regarding the accuracy of the correction still have to be carried out.