ABSTRACT

The purpose of this work is to test a possible system for treatment of patients carrying the most common mutation in the severe Dowling-Meara form of epidermolysis bullosa simplex (EBS). Ribozyme genes are small artificial genes that can be designed to switch off other genes, such as a gene causing a dominant type of EB. Dr McLean’s group has recently developed a ribozyme gene that can specifically switch off the mutated keratin 14 gene that causes EBS in mice. In this project, the successful mouse ribozyme will be adapted to target the equivalent mutation in humans that causes severe Dowling-Meara EBS. Two strategies will be used. First, a ribozyme gene will be made to target the EBS mutation. This will be tested in vitro and in cells from patients carrying the appropriate EBS mutation. This system could be developed into a method for ex vivo gene therapy. Secondly, a smaller version of the therapeutic ribozyme molecule will be synthesised using newly developed chemical techniques and this will also be tested in vitro and in patient cells. If these synthetic ribozymes work as well as ribozyme genes, they might be suitable for development of a topically applied form of gene therapy for EBS, i.e. "gene cream". Collectively, these experiments will pave the way for treatment of EBS and other dominant forms of EB.

FINANCIAL SUMMARY