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AssigneeUniversity of Pittsburgh—Of the Commonwealth System of Higher Education
InventorsAl-Walid A. Mohsen, Gerard Vockley
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Methods of treating mitochondrial fatty acid b-oxidation and/or transport disorders arising from mutant proteins in the mitochondrial fatty acid β-oxidation and transport metabolic pathways in patients are provided. The methods modulate the mitochondrial fatty acid β-oxidation pathway at the last step so that the product of the mutant protein accumulates and stabilizes the mutant protein and/or the substrate(s)/product(s) of the down stream reactions accumulate and possibly bind to allosteric sites on the mutant protein to stabilize it. Trimetazidine pharmacodynamics function as such in the β-oxidation pathway. Further, a synergistic effect is observed where trimetazidine and PPARδ agonist combination enhanced enzyme activity and presence significantly more than either alone.
A method of treating a disorder caused by a missense mutation in any of the enzymes/proteins of the β-oxidation pathway or fatty acid mitochondrial transport in a patient in need thereof, comprising administering to the patient an effective amount of an inhibitor of activity of an enzyme of the β-oxidation pathway downstream in the β-oxidation pathway of the enzyme having the mutation, thereby increasing activity of the enzyme of the β-oxidation pathway of fatty acid mitochondrial transport having the mutation, wherein the product, optionally a reverse reaction substrate, of the enzyme having the mutation stabilizes that unstable enzyme, or one or more substrates or products of the downstream enzyme binds allosterically to the mutant enzyme and stabilize that unstable enzyme.
A method of increasing activity of an enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme, the protein/enzyme having a mutation resulting in loss of its activity or stability, in a patient in need thereof, comprising administering to the patient an effective amount of an inhibitor of activity of an enzyme of the β-oxidation pathway downstream in the β-oxidation pathway of the enzyme having the mutation, thereby increasing activity of the upstream enzyme of the β-oxidation pathway or a fatty acid mitochondrial transporter protein/enzyme having a mis sense mutation, wherein the product, optionally a reverse reaction substrate, of the enzyme having the mutation binds and stabilizes that protein/enzyme.
Dependencies are inferred from the claim text.