Novel Treatment Options
During the first funding period, we exchanged mouse models to test new therapeutic strategies and established a tool for the generation of transgenic mice. Now we will focus on the development of a promising therapeutic approach which has the potential to be applicable for a large group of patients with mutations in either nuclear or mitochondrial genomes that give raise to complex I defect, the most frequent biochemical diagnosis. We will apply strategies to bypass the complex I deficiency by utilizing alternative NADH dehydrogenases by transgenic proof-of-principle combined with a therapy-directed protein transduction approach. The feasibility of a bypass approach has been demonstrated in cell lines by us and others. In vivo approaches have been not described yet for complex I bypassing in mouse. To test the feasibility of this approach, we will address the following specific objectives:
i) to examine genetic expression of alternative NADH dehydrogenase NDI1 and NDH2 as complex I bypassing strategy in murine models,
ii) to assess mitochondrial protein transduction of alternative NADH dehydrogenase NDI1 and NDH2 as complex I bypassing strategy in murine models .