Compositions and methods for the modulation of mitophagy for use in treatment of mitochondrial disease
AssigneeThe Children's Hospital of Philadelphia
InventorsMarni J. FALK, Suraiya HAROON
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Abstract
Compositions and methods for modulation by upregulation (up modulation) and/or downregulation (down modulation) of mitophagy are described for the treatment of mitochondrial disorders including OPA-1 related disease and Single Large Scale Mitochondrial DNA Deletion (SLSMD). Also disclosed are a number of screening assays and gene targets having utility for the identification of agents which modulate the phenotype associated with such disorders.
Claims27
A composition which modulates at least one of mitophagy mitochondrial stress level, and mtDNA heteroplasmy level having efficacy for the treatment of mitochondrial disease, comprising effective amounts of one or more agents selected from hemin, tripterin, folinic acid, lithium chloride, metformin, N-acetylcysteine, nicotinamide, resveratrol, valproic acid, dexamethasone, etoposide, vorinostat, quercitin, hydralazine, thiamine, lipoic acid, pfithrin-alpha, ginsenoside, sulfonsuccinimidyl oleate, carnitine, AICAR, GSK2578215A, an inhibitory nucleic acid and an activating genetic construct targeting a mitophagy modulator protein encoding nucleic acid in a pharmaceutically acceptable formulation.
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A screening method for identifying agents which modulate mitophagy, comprising;
- a) providing genetically altered C. elegans, said genetic alteration impacting a gene associated with mitophagy, and wild-type C. elegans, lacking said genetic alteration;
- b) contacting the C. elegans from step a) with an agent;
- c) determining whether said agent alters a cellular parameter associated with mitophagy pathway activity(s) in C. elegans comprising said genetic alteration relative to wild type C. elegans;
- agents which alter said parameter in said genetically altered C. elegans being identified as modulators of mitophagy wherein said C. elegans is optionally contacted with a stressor prior before, after, or concomitantly with said agent.
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A humanized C. elegans strain expressing a mutated OPA1 mitophagy modulator protein, said mutation being selected from eat-3(R289Q) or eat-3(V328I).
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Dependencies are inferred from the claim text.