Mitochondrial diseases are common and devastating conditions with an extremely poor prognosis. Gene therapies have been proposed involving allotopic expression of recoded mitochondrial genes from the nucleus, however, the viability of such an approach remains controversial. We have discovered that the major technical hurdles to such an approach that limit the development of a novel gene therapy are competition from the endogenous mutant protein in the complex and the hydrophobicity of these proteins. We have discovered a novel mitochondrial translation inhibition (TLI) approach to prevent expression of the mutant protein within mitochondria. We propose to test the combination of mitochondrial TLI with a novel therapy approach that targets coding RNAs to mitochondria. Such an approach directly addresses both technical hurdles using novel and previously untested methods. Any serious investigation aimed at developing a novel mitochondrial gene therapy would require a well-characterized, pathogenic, endogenous mitochondrial mutation in an amenable genetic system where feasibility can be demonstrated and optimized in vivo. We propose a rigorous test of mitochondrial TLI and mitochondrial-targeted RNA expression using several biochemical and phenotypic assays of function in a well-characterized animal model system.
Mitochondrial diseases are devastating untreatable diseases that affect ~1 in 3-5000 humans. We propose preclinical research to develop and demonstrate efficacy of a novel mitochondrial-targeted RNA approach as a viable gene therapy. This approach will be developed and tested in vitro in human cells and in vivo using an established invertebrate genetic model of mitochondrial disease.
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