Drug Candidate Revives Mice in Rare Kidney Disease Study

N-propargylglycine (N-PPG) prevents kidney stones and restores survival in a lethal mouse model of Primary Hyperoxaluria Type 2

Apr. 3, 2026 at 6:26am by Ben Kaplan

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A highly structured abstract painting in soft blues, greens, and grays, featuring sweeping geometric arcs, concentric circles, and precise botanical spirals, conceptually representing the complex scientific forces and metabolic processes behind the rare kidney disease Primary Hyperoxaluria Type 2.A novel drug candidate that targets a key enzyme in the metabolic pathway responsible for Primary Hyperoxaluria Type 2 could offer a much-needed therapy for this rare and deadly genetic disorder.San Francisco Today

Scientists at the Buck Institute for Research on Aging have shown that an orally administered small molecule, N-propargylglycine (N-PPG), can completely prevent the formation of calcium oxalate kidney stones, protect against kidney failure, and fully restore normal survival in a mouse model of Primary Hyperoxaluria Type 2 (PH2), a rare and currently untreatable genetic disorder that causes progressive kidney failure in infants and young adults.

Why it matters

Primary hyperoxaluria is a group of rare inherited metabolic disorders that have no therapeutic options, often leading to kidney and liver transplantation. The Buck Institute's discovery of N-PPG as a potential treatment for PH2 represents a significant step toward a much-needed therapy for this lethal disease.

The details

N-PPG targets a key enzyme called hydroxyproline dehydrogenase (HYPDH/PRODH2) that catalyzes the first step in breaking down hydroxyproline, an amino acid derived from collagen turnover. By blocking HYPDH/PRODH2, N-PPG cuts off the excess oxalate production at its source, preventing its damaging precipitation as calcium oxalate kidney stones.

  • In an initial three-week study, N-PPG treatment significantly reduced urinary oxalate levels and nearly eliminated calcium oxalate stone formation in mice with PH2.
  • In a landmark six-month survival study, the PH2 mice treated daily with oral N-PPG survived the full 24 weeks of the study, with survival, weight, and kidney function indistinguishable from normal healthy wild-type controls.

The players

Buck Institute for Research on Aging

A research institute located in San Francisco, California that focuses on studying mechanisms of aging and identifying therapeutics that slow down aging.

Gary Scott, PhD

A senior scientist studying breast cancer in the Benz lab at the Buck Institute.

Lisa Ellerby, PhD

A neuroscientist at the Buck Institute who studies Huntington's and Alzheimer's disease.

Christopher Benz, MD

A professor at the Buck Institute and an oncologist who never envisioned going in the direction of neurodegeneration or kidney stones.

N-propargylglycine (N-PPG)

An orally administered small molecule that can completely prevent the formation of calcium oxalate kidney stones, protect against kidney failure, and fully restore normal survival in a mouse model of Primary Hyperoxaluria Type 2.

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What they’re saying

“What's exciting about N-PPG is that it has a dual mechanism of action. It not only inhibits PRODH2, a key enzyme in the pathway that generates oxalate, but it also induces mitohormesis, a beneficial stress response that strengthens mitochondrial resilience. So, we're not just reducing the toxic oxalate burden; we're also making the kidney more resilient to any damage it might cause.”

— Lisa Ellerby, Professor

“N-PPG appears to be an amazing drug candidate, not just because it's orally bioavailable and penetrates many different tissues without producing any side effects, but in addition to treating PH2 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.”

— Christopher Benz, Professor

What’s next

Future studies are planned to evaluate N-PPG in PH3 models once improved animal models become available. Additional pharmacokinetic and safety studies are still needed before advancing to clinical development. As well, additional chemical analogs are under development to understand the kidney mitohormesis benefit of N-PPG relative to simply reducing liver oxalate production with a selective HYHPDH/PRODH2 inhibitor.

The takeaway

The Buck Institute's discovery of N-PPG as a potential treatment for the rare and lethal Primary Hyperoxaluria Type 2 disease represents a significant breakthrough, as this genetic disorder currently has no therapeutic options and often leads to kidney and liver transplantation. The dual mechanism of action of N-PPG, both reducing oxalate production and strengthening mitochondrial resilience, suggests it may have broader applications beyond just PH2.