Cells in patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency are able to use C7-coA as a substrate, mostly due to short-chain acyl-CoA dehydrogenase (SCAD) activity.

Moreover, C7, or triheptanoin, is able to correct the imbalance in lipid metabolism and improve glycogen metabolism in the liver of mice deficient in MCAD.

These are the results of a study by Al-Walid Mohsen, UPMC-CHP, and colleagues as presented at the 2022 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM).


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According to Dr. Mohsen, these results provide the basis for a clinical trial testing C7 as a potential treatment for MCAD deficiency. 

MCAD is characterized by the inability of the body to break down fatty acids with 6 to 10 carbon atoms. One key to the pathophysiology of fatty acid oxidation disorders, including long-chain fatty acid oxidation disorders (LCFAOD) is the diminished supply of succinyl-CoA in the Krebs’s cycle. So, replenishing succinyl CoA holds therapeutic promise.

Read more about the differential diagnosis of LCFAODs.

Here, Dr. Mohsen and colleagues conducted experiments using cells from patients with MCAD grown in culture and mice deficient in MCAD to test the efficacy of heptanoate and its derivatives as a potential therapy for the disease.

The results showed that heptanoic acid improved intracellular succinate and propionate levels. Among medium branch-chain fatty acids, AdMC7 performed the best. This, Dr. Mohsen said, suggests that AdMC7 could be a viable water-soluble alternative to C7. “Future in vivo testing of this compound is planned”, he added.

C7 also improved the bioenergetic parameters of fibroblast cells from patients with MCAD deficiency as did dMC7, AdMC7, and to a greater degree dMC9.

The animal experiments showed that triheptanoin decreased steatosis and increased glycogen storage in the liver of MCAD-deficient mice, making it a promising potential therapeutic agent if proven to be well tolerated in humans.

MCAD deficiency and LCFAOD are both types of fatty acid oxidation disorders. MCAD deficiency can be differentiated from LCFAODs based on in vitro fatty acid oxidation rate studies. Triheptanoin is approved by the US Food and Drug Administration (FDA) for the treatment of patients with LCFAOD.

Reference

Mohsen AW. Preclinical evidence of efficacy of heptanoate and derivatives as anaplerotic therapy for medium chain acyl-CoA dehydrogenase deficiency. Lecture presented as part of International Network for Fatty Acid Oxidation Research and Management (INFORM) 2022 lecture series: February 14, 2022; Virtual.