University of Pittsburgh

Gerard Vockley

Al-Walid A Mohsen

Al-Walid Mohsen Mohamed

Peter Wipf

Methods of treating propionic acidemia (PA), methylmalonic acidemia (MMA) and fatty acid oxidation disorders are described. The methods include administering an anaplerotic agent that can directly enter the tricarboxylic acid cycle, such as a succinate derivative or pro-drug, for example trisuccinylglycerol (TSG). Methods of restoring tricarboxylic acid (TCA) cycle function in a cell deficient for propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT) by contacting the cell with a succinate derivative or pro-drug, such as TSG, are also described.

Anaplerotic agents for treatment of disorders of propionate and long chain fat metabolism

Methods of treating a patient having an organic acidemia or a defect in mitochondria chain oxidation are provided. The methods comprise treating the patient with an effective amount of a mitochondria-targeting reactive oxygen species scavenger.

Method of treatment of organic acidemias and other mitochondria defects or deficiencies

Methods of treating mitochondrial fatty acid &#x3b2;-oxidation and/or transport disorders arising from mutant proteins in the mitochondrial fatty acid &#x3b2;-oxidation and transport metabolic pathways in patients are provided. The methods modulate the mitochondrial fatty acid &#x3b2;-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 &#x3b2;-oxidation pathway. Further, a synergistic effect is observed where trimetazidine and PPAR&#x3b4; agonist combination enhanced enzyme activity and presence significantly more than either alone.

Therapy for mitochondrial fatty acid beta-oxidation and transport disorders

Methods of treating mitochondrial fatty acid b-oxidation and/or transport disorders arising from mutant proteins in the mitochondrial fatty acid &#x3b2;-oxidation and transport metabolic pathways in patients are provided. The methods modulate the mitochondrial fatty acid &#x3b2;-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 &#x3b2;-oxidation pathway. Further, a synergistic effect is observed where trimetazidine and PPAR&#x3b4; agonist combination enhanced enzyme activity and presence significantly more than either alone.

Provided herein are methods of measuring acyl-CoA dehydrogenase activity in a biological sample in a multiwell microplate setting.

Acyl-CoA dehydrogenases micro/nano enzyme assay

The present invention provides for methods and compositions for treating medium chain acyl-CoA dehydrogenase deficiency. It is based, at least in part, on the discovery that phenylbutyrate can serve as a substrate for medium chain acyl-CoA dehydrogenase. In non-limiting embodiments, phenylbutyrate and/or another source of phenylacetate is administered as a chaperone treatment to patients suffering from medium chain acyl-CoA dehydrogenase deficiency.

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Pittsburgh, PA, United States of America

Gerard Vockley