Mitochondrial Allotopic Gene Therapy Approaches Using a Drosophila Model with an Endogenous ATP6 Mutation

[摘要] Mitochondrial Encephalomyopathies are a group of disorders with common symptoms such as neurological, cardiac, and muscular dysfunctions. Mutations in ATP6, a protein-coding gene in the mitochondria genome, can lead to NARP, MILS, or FBSN diseases. ATP6 encodes a protein subunit of the ATP synthase, also known as complex V. Currently, there is no cure for patients with ATP6 mutations, and pharmacotherapies provide limited benefits. Because manipulation of mitochondrial genome is extremely difficult, allotopic expression of ATP6 – specifically, expressing the mitochondrially-encoded ATP6 gene in the nucleus – has been championed as a potential gene therapy strategy. Efficacies of allotopic rescue in in vitro systems have been controversial, with some studies showing the restoration of ATP synthase activity and some showing the lack of any rescue effects. We have isolated a Drosophila strain with a missense mutation in ATP6. The phenotypes of this mutant ATP6 strain have been characterized and are very similar to those of human patients, making it an excellent model for diseases caused by ATP6 mutation. The overarching goal of this dissertation is to import nucleus-encoded ATP6 protein into the mitochondria. This work examines the efficacies of multiple strategies in enhancing the functional outcomes of the first animal model with a stable and endogenous ATP6 mutation and shows that algal ATP6 protein provides the most promising rescue results.

[发布机构] the University of Pittsburgh