Exon skipping therapy for dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa (DEB) is a heritable skin blistering disease also called butterfly disease, which is caused by mutations in the COL7A1 gene. This gene encodes the type VII collagen protein which secures attachment of the epidermis to the underlying dermis, like Velcro. Defects in this protein result in blistering of the skin and mucosae upon the slightest friction. The most severe form of DEB is caused by the complete absence of type VII collagen protein. Patients suffering from this severe type die young, as result of complications of the disease. Currently, there is no curative therapy available and treatment is focussed on easing symptoms. The first step towards a curative therapy for DEB was made in this thesis. Exon skipping therapy makes use of specific synthetic RNA-molecules to skip the mutation together with its surrounding code (exon) from the RNA chain. First, we showed feasibility of exon skipping in cultured patient cells. Subsequently, this was successfully translated into a mouse model. In this model, skin of a patient was grown on the back of mice. Afterwards, these mice were treated by injections of the synthetic RNA-molecules. This was successful as type VII collagen was observed in the treated patient skin on the back of these mice. The overall conclusion of this thesis research was that exon skipping therapy is suitable for the most severe form of DEB, and that further investigation in optimization is required. In his thesis, the path from bench to bedside is described, outlining future research.