Research finds novel treatment method for propionic acidemia

Sep, 2021 - By WMR

Pantazines drug will be the first targeted propionic acidemia therapy based on modulating pantothenate kinases to control propionyl-CoA carboxylase levels.

Researchers at St. Jude Children's Research Hospital have demonstrated that a drug class they invented has the potential to cure propionic acidemia, a rare metabolic condition. Mutations in the enzyme propionyl-CoA carboxylase cause propionic acidemia. CoA is a cofactor molecule that is required for energy metabolism. Diet is primarily used to treat propionic acidemia. The study identifies mitochondrial dysfunction as a major contributor to propionic acidemia. Doctors track metabolites in the blood to get a notion of how severe a condition is.

This research adds to the knowledge of mechanisms that cause changes in these metabolites, implying that some of them are caused by cells attempting to compensate for CoA depletion. This discovery expands on the findings of a group of St. Jude researchers who uncovered new treatments for pantothenate kinase-associated neurodegeneration, a rare condition (PKAN). Both PKAN and propionic acidemia are metabolic diseases in which CoA metabolism is important. While working on PKAN, St. Jude researchers developed a class of drugs known as pantazines, which are based on a substance discovered through a screen of over 500,000 tiny molecules.

Once screening hits are identified, developing compounds to therapeutically target a specific source of the disease is a sophisticated process in which several competing aspects must be balanced. Pantazines were carefully designed to raise cellular CoA levels, penetrate the blood-brain barrier, be effective when taken as a tablet, and have minimal adverse effects.

Pantazines are small-molecule activators with the potential to treat a variety of metabolic inborn genetic disorders. The researchers mapped out the metabolic network through their work on propionic acidemia, demonstrating how pantazines enhance CoA and hence improve mitochondrial function and cell health.