Advances in the development of the trans-splicing therapy for DEB: correction of collagen 7 mutations by direct application onto the skin
New scientific publication by the Koller working group from the EB House Austria
Inherited mutations in the collagen 7 gene lead to the production of a faulty collagen 7 protein or its’ complete lack in skin cells of individuals suffering from dystrophic EB (DEB). The result is an impaired cohesion of the skin layers often accompanied with massive blistering. There is a clear medical need for patients with severe recessively inherited DEB (RDEB) forms, but also for those affected with dominant DEB (DDEB), who usually show milder localized blistering. So far, therapy development has not been a focus for DDEB patients, and they are currently excluded from gene therapies. The trans-splicing therapy has the potential of a causative treatment for all forms of DEB.
This technology specifically repairs the defective section of the collagen 7 gene transcript in DEB skin cells, resulting in the formation of a functioning collagen 7 protein, and thus the cohesion of the skin layers. Scientists of the EB house have developed this technology for many years and designed two potent repair molecules (RTMs) that replace either the anterior or posterior mutated section of the collagen 7 gene transcript in the skin cells with a correct one. In the course of a clinical application, one of these RTMs is introduced into the skin cells, depending on where in the gene the mutation is located.
Now the EB house scientists have developed a pain-reduced method in which the RTM can repair the defective gene transcript directly in the skin (in situ). Here, the RTM is packaged into a DNA transporter that does not contain any viral DNA and therefore does not remain permanently in the cell as is the case with the gene replacement therapy already applied. Thus, the risk of a negative modification of the cell's own DNA is minimized. In order to introduce the molecule efficiently into the skin cells, it is loaded onto liposomes. These are tiny spheres whose wall consists of fatty substances, similar to the cell wall. So, when the liposomes reach the skin cells, they fuse together, releasing their load into the cell. Thus, by simply dropping the molecule-liposome complex onto skin wounds, gene correction could take place in the skin cells.
This was tested in the laboratory using a model system of artificially grown RDEB skin. The researchers were able to prove successful correction through the trans-splicing method, as a healthy collagen 7 protein was produced between the skin layers. Although there are still many steps to take before it can be applied in clinics, this study has laid the ground for a possible in situ trans-splicing treatment method for RDEB and DDEB patients.