Repurposing known drugs to identify potential therapeutics for Leber's hereditary Optic Neuropathy: screening in cells and testing in a mouse model of LHON.

摘要

Purpose : The purpose of the experiments is to identify potential therapeutics for LHON, a blinding, inherited mitochondrial disease with no currently-FDA-approved therapy. Methods : High-throughput screening was carried out of 1600 FDA-approved molecules in LHON cell models. Testing multiple mechanisms of action was carried out for identified hits with inhibitors and tests of mitochondrial physiology. We previously characterized a mouse model of LHON and mitochondrial blindness, the Ndufs4 mouse. Validated drug Hits from the HTS screen were tested for their ability to suppress the 'inflammatory wave' that precedes vision loss in the Ndufs4 mouse, and also the vision loss itself, by visual cliff assays, and by neuropathological/histopathological analysis. Results : Multiple FDA-approved drugs were identified that rescued LHON-dependent defects in cells, i.e. they were protective in cell models, and increased mitochondrial complex 1-dependent ATP synthesis. Mechanistic testing suggested at least partial involvement of cyclic AMP cascade. Drugs were tested in Ndufs4KO mouse for their ability to suppress the inflammatory wave that precedes vision loss, and the vision loss itself. Multiple drugs rescued vision loss in the context as measured by visual cliff, and at least one appeared to rescue retinal cell death that precedes vision loss. Conclusions : These results suggest that a repurposing approach can identify potential LHON therapeutics. Complete mechanisms of action are still unclear, however the drugs have been used by millions of people safely, removing a major barrier for future clinical trials. Additive positive effects are observed in cells but have not yet been tested in animals. Drugs were given i.p. in mice, and should be further tested with respect to dose and route of administration, including as eyedrops, to determine maximal effectiveness, formulation and best route of administration. These drugs could be considered leads for future therapy for human patients with LHON. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.