Scientists at the Buck Institute for Research on Aging announced on Apr. 2 that an orally administered small molecule, N-propargylglycine (N-PPG), prevented calcium oxalate kidney stones and restored normal survival in a mouse model of Primary Hyperoxaluria Type 2 (PH2). PH2 is a rare genetic disorder that causes progressive kidney failure, primarily affecting infants and young adults.
The findings are important because PH2 currently has no available treatments, with patients often facing severe outcomes such as end-stage kidney failure or organ transplantation. The research offers hope for new therapies targeting this life-threatening disease.
According to the study published in Kidney International, N-PPG blocks a key enzyme called hydroxyproline dehydrogenase (HYPDH/PRODH2) involved in producing oxalate, which forms damaging crystals in the kidneys. By inhibiting this enzyme, researchers were able to stop excess oxalate production at its source. In initial studies lasting three weeks, mice treated with N-PPG showed reduced urinary oxalate levels and almost no stone formation compared to untreated animals. A six-month survival study further demonstrated that treated mice had normal weight and kidney function throughout the experiment while untreated mice died from renal failure.
The research was sparked by collaboration between scientists studying different diseases who discovered N-PPG's potential after discussing its effects on mitochondrial function. "What's exciting about N-PPG is that it has a dual mechanism of action," said Professor Lisa Ellerby PhD. "It not only inhibits PRODH2... but it also induces mitohormesis... So we're not just reducing the toxic oxalate burden; we're also making the kidney more resilient to any damage it might cause." Buck professor Christopher Benz MD said: "N-PPG appears to be an amazing drug candidate... its mitohormetic properties may extend its utility to the prevention of more common forms of recurrent CaOx kidney stone disease and perhaps even to other organ disorders benefitting from strengthened mitochondrial resistance."
The researchers believe N-PPG could also help patients with Primary Hyperoxaluria Type 3 due to similarities in metabolic pathways. Future studies are planned once improved animal models become available.
Previous studies have shown good tolerability for N-PPG over six months without significant side effects in mice, though further safety testing is required before clinical development can begin.
