Mitochondrial RNA transport as a novel therapy

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DESCRIPTION (provided by applicant): Archetypical mitochondrial diseases are common and devastating conditions with an extremely poor prognosis. Gene therapies have been proposed including allotopic expression of recoded mitochondrial genes from the nucleus. The extreme hydrophobicity of mitochondrial-encoded proteins remains a technical hurdle to such therapies. We propose a novel allotopic gene therapy approach where the RNA is actively transported into mitochondria for translation. We have developed vectors that express stable, transportable RNAs and will test their efficacy in vivo. Any serious investigation aimed at developing allotopic expression as a 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 RNA transport using both biochemical and phenotypic assays of function using a well-characterized model animal system. PUBLIC HEALTH RELEVANCE: 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 RNA transport gene therapy. This approach will be developed and tested in vivo using an established invertebrate genetic model of mitochondrial disease.