Triheptanoin: targeting the Krebs cycle in Huntington’s disease

Triheptanoin, a synthetic medium-chain triglyceride, acts as an anaplerotic compound for the Krebs cycle. It breaks down into acetyl-CoA and propionyl-CoA which can replenish the Krebs cycle via succinyl-CoA. Fanny Mochel, MD, PhD, APHP, Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France, discusses the rationale behind the development of triheptanoin as a treatment option in Huntington’s disease (HD) and shares evidence from the 6-month randomized, controlled, bicentric TRIHEP3 trial (NCT02453061). Prior investigations have shown that energy deficiencies seen in HD are associated with increased substrate requirements for the Krebs cycle. Observed decreases in branched-chain amino acids, precursors of acetyl-CoA and succinyl-CoA, led to the hypothesis that the body was trying to compensate for an energy deficiency by using these amino acids to keep the Krebs cycle running. Therefore, the ability of triheptanoin to improve energy homeostasis through acetyl-CoA and propionyl-CoA supply was investigated. Treatment with triheptanoin for 12 months was associated with stabilization of Unified Huntington’s Disease Rating Scale (UHDRS) scores and decreased caudate atrophy. This interview took place during the 2021 International Congress of Parkinson's Disease and Movement Disorders.