An orally administered small molecule called N-propargylglycine, or N-PPG, completely prevented calcium oxalate kidney stone formation, protected against kidney failure, and restored normal survival in a mouse model of Primary Hyperoxaluria Type 2, according to scientists at the Buck Institute for Research on Aging. The results were published in Kidney International.
PH2 belongs to a group of rare inherited metabolic disorders in which the body overproduces oxalate, a compound that crystallizes with calcium in the kidneys. Those crystals drive recurrent stones, progressive kidney damage and, in severe cases, end-stage kidney failure in infants and young adults. Roughly 1,700 people in the US are estimated to have the disease, though researchers suspect many cases go undiagnosed. Patients with the more common Type 1 form now have two approved RNA-based therapies that work partially, but those with Type 2 and Type 3 have no treatment options at all and often face kidney and liver transplantation to extend survival.
The Buck approach goes after the problem upstream. An enzyme known as hydroxyproline dehydrogenase, or HYPDH/PRODH2, sits in liver and kidney mitochondria and starts the breakdown of hydroxyproline, an amino acid that comes largely from collagen turnover. That breakdown yields glyoxylate, which PH2 patients cannot properly metabolize, so it converts to excess oxalate instead. Blocking the enzyme with N-PPG shuts off the oxalate supply at its origin, before it can precipitate as stones.
Notably, the work grew out of a collaboration between Buck scientists whose primary focus was breast cancer and Huntington's disease - a reminder of how often rare-disease leads emerge sideways from unrelated laboratories. The findings so far come from mice, and the researchers describe the result as a significant step toward a therapy rather than a finished one, but for a lethal metabolic disorder with nothing on the shelf, an oral compound that normalizes survival in an animal model is a meaningful starting point.