Maternally inherited diseases associated with mutations in mitochondrial DNA are generally multisystemic, typically affecting the central nervous system, heart, skeletal muscles and endocrine glands. It has been difficult to understand the pathogenic processes associated with such disorders, much less to develop treatments, because of the lack of animal models that recapitulate the characteristics of mitochondrial disease. In recent years, we have succeeded in using the toots of gene therapy, namely the viral-mediated transfer of ribozymes, to create animal models with a common feature of many mitochondrial diseases - optic nerve degeneration. Ribozymes specific for a nucleus-encoded subunit (NDUFA1) of Complex I of the mitochondrial respiratory chain lead to damage similar to that seen in Leber Hereditary Optic Neuropathy, the most common inherited mitochondrial disease. We have recently demonstrated similar pathology using a ribozyme targeted to another subunit (ND4) of the same enzyme that is produced within mitochondria. In this proposal, we plan to develop mouse models that capture another mitochondrial disorder called NARP and to take the first steps toward gene therapy of these devastating diseases. We propose: (1) To develop ribozymes that can be delivered to mitochondria to create mouse models with deficits in the ATP6 subunit of the mitochondrial ATP synthase (Complex V); and (2) To treat the animal models developed by ribozyme knockdown of ATP6 and ND4 by delivering nuclear genes that replace the deficient mitochondrial gene product, a procedure termed allotopic expression. Since it has already been established that allotropic expression can rescue mitochondrial defects in cultured cells, our second aim stands independently of the first: It is important to test allotopic expression in animal tissues that are typically affected in mitochondrial disease. While we are testing specific hypotheses concerning how mitochondrial damage causes retinopathy and optic neuropathy, our ultimate aim is developing treatments - either genetic or pharmacological - for mitochondrial disease. ? ?
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