survived the entire 24 weeks with kidney function indistinguishable from healthy mice
In the shared corridors of the Buck Institute for Research on Aging, a casual exchange between a cancer researcher and a neuroscientist has produced something the medical world has never offered the roughly 1,700 Americans living with Primary Hyperoxaluria Type 2: a genuine therapeutic hope. The oral molecule N-PPG, originally studied for its effects on cancer and neurodegeneration, was found to block the precise enzymatic step that floods kidneys with oxalate crystals — and in doing so, it granted complete survival to mice that would otherwise have died of renal failure within months. The discovery reminds us that the boundaries we draw between disciplines are often more administrative than biological, and that proximity, curiosity, and a willingness to follow evidence across those boundaries can quietly change the course of a disease.
- For patients with PH2 — many of them infants and young adults — the disease has moved in only one direction: toward kidney failure, transplantation, and a shortened life, with no approved treatment to interrupt its course.
- A molecule being studied for cancer quietly revealed a second identity, blocking the liver and kidney enzyme responsible for the excess oxalate production that turns kidneys into stone-filled organs.
- In a six-month survival study, every treated mouse lived the full duration with normal kidney function, while nearly all untreated mice died within 15 weeks — a gap so stark it reframes what intervention might mean for human patients.
- The compound's dual action — cutting off oxalate at its metabolic source while simultaneously fortifying mitochondrial resilience — suggests it may work not only for PH2 but for related subtypes and potentially common kidney stone disease.
- Before human trials can begin, researchers must complete pharmacokinetic and safety studies, and are already developing chemical analogs to sharpen their understanding of exactly which properties of N-PPG produce the kidney benefit.
A chance conversation in a shared lab at the Buck Institute for Research on Aging has produced a potential treatment for a disease that has never had one. Primary Hyperoxaluria Type 2 is a rare inherited disorder that causes the body to overproduce oxalate, a compound that crystallizes in the kidneys and drives relentless progression toward organ failure. About 1,700 Americans carry the diagnosis, though many more cases likely go undetected. Until now, transplantation has been the only recourse.
Gary Scott, a senior scientist studying breast cancer, was investigating a small oral molecule called N-PPG when he mentioned his findings to neuroscientist Lisa Ellerby, whose lab occupied the adjacent space. Scott had observed that N-PPG appeared to strengthen cellular function through mitohormesis — a mild stress response that fortifies cellular machinery. When Ellerby's team tested it on cells modeling Huntington's disease, it corrected roughly half the associated genetic expression problems. As both teams examined the mechanism more closely, they recognized that N-PPG was acting on the same metabolic pathway that generates excess oxalate. They pivoted toward kidney disease.
The results, published in Kidney International, were decisive. In a short-term study, N-PPG nearly eliminated calcium oxalate stone formation in PH2 mice and preserved kidney function. The six-month survival study was more striking still: untreated mice died of renal failure within a median of 15 weeks, while mice receiving daily oral N-PPG survived the entire 24-week study with kidney function and body weight indistinguishable from healthy animals.
The mechanism works at the source. PH2 patients cannot properly metabolize hydroxyproline, an amino acid released during collagen breakdown, leading to excess glyoxylate that the body converts to oxalate. N-PPG blocks the enzyme HYPDH/PRODH2, which initiates that breakdown in liver and kidney mitochondria — cutting off excess oxalate production before it begins. The molecule also triggers mitohormesis, giving kidneys added resilience against whatever oxalate damage does occur. It is a two-pronged intervention.
The compound is orally bioavailable, penetrates multiple tissues, and has shown no significant adverse effects across studies lasting up to six months in mice. Because PH2 and the related subtype PH3 share the same metabolic pathway, N-PPG may eventually address both. Further safety and pharmacokinetic studies are needed before human trials, and the team is developing chemical analogs to refine their understanding of the compound's action.
What began as a neighborly exchange between scientists working on entirely different diseases has opened a door that seemed permanently shut. The discovery also reflects something the researchers themselves emphasize: that the interdisciplinary proximity rare in larger institutions can produce exactly this kind of unexpected convergence. Scott and Ellerby were not searching for a kidney stone cure. They were simply willing to follow the data, and to listen.
A chance conversation between two researchers sharing lab space at the Buck Institute for Research on Aging has yielded something unexpected: a potential cure for a disease that has no treatment. Primary Hyperoxaluria Type 2, or PH2, is a rare inherited metabolic disorder that strikes infants and young adults without warning, causing their bodies to overproduce oxalate—a compound that crystallizes in the kidneys as calcium oxalate stones. The disease progresses relentlessly toward kidney failure. An estimated 1,700 people in the United States carry the diagnosis, though many more cases likely go unrecognized. Until now, there has been nothing to offer them but the prospect of transplantation and a shortened life.
Gary Scott, a senior scientist studying breast cancer, was examining a small molecule called N-propargylglycine (N-PPG) as a potential cancer treatment when he mentioned his findings to Lisa Ellerby, a neuroscientist working on Huntington's and Alzheimer's disease in the adjacent lab. Scott had noticed that N-PPG seemed to improve cell function through a process called mitohormesis—a mild stress response that strengthens cellular machinery. Ellerby suggested testing it on cells modeling Huntington's disease. It worked, correcting about half the genetic expression problems associated with the neurological condition. As the two teams dug deeper into the mechanism, they realized N-PPG was affecting the metabolic pathway that generates oxalate. The conversation shifted. They decided to test it in kidney disease.
The results, published in Kidney International, are striking. In a three-week study, N-PPG treatment reduced urinary oxalate levels and nearly eliminated calcium oxalate stone formation in mice engineered to have PH2. The treated animals showed far less kidney damage and better-preserved kidney function than their untreated counterparts, whose kidneys rapidly filled with stones and deteriorated. But the six-month survival study delivered the real proof. Untreated PH2 mice fed a diet high in hydroxyproline—designed to mimic the human disease—survived a median of 15 weeks before dying of kidney failure. Nearly all of them died. The mice treated daily with oral N-PPG, by contrast, survived the entire 24 weeks of the study. Their survival, weight, and kidney function were indistinguishable from healthy mice.
The mechanism is elegant. PH2 patients cannot properly metabolize hydroxyproline, an amino acid released when the body breaks down collagen. This failed metabolism produces excess glyoxylate, which the body converts to oxalate. N-PPG blocks a key enzyme called hydroxyproline dehydrogenase (HYPDH/PRODH2) that resides in liver and kidney mitochondria and catalyzes the first step of hydroxyproline breakdown. By shutting down this enzyme, the researchers cut off excess oxalate production at its source. But N-PPG does something else too: it triggers mitohormesis, strengthening the kidney's resilience against whatever damage oxalate might cause. It is, in effect, a two-pronged attack.
Christopher Benz, an oncologist and Buck professor, notes that N-PPG is orally bioavailable—patients can take it as a pill—and penetrates multiple tissues without producing side effects in the mouse studies conducted so far, some lasting up to six months. The compound has shown no significant adverse effects on health, activity, body weight, or organ function. Because both PH2 and PH3, another subtype of primary hyperoxaluria, depend on the same metabolic pathway to generate excess oxalate, N-PPG may eventually treat both forms of the disease. The researchers acknowledge that further pharmacokinetic and safety studies are needed before human trials can begin, and they are developing additional chemical analogs to better understand which aspects of N-PPG's action produce the kidney benefits.
What began as a casual conversation between neighbors in a shared lab space has opened a door that seemed permanently closed. For patients with PH2 and their families, who have watched the disease progress without recourse, the implications are profound. The discovery also speaks to something less tangible but equally important: the value of the kind of collaborative, interdisciplinary research that Benz says is rare in larger academic institutions. Scott and Ellerby were not looking for a kidney stone cure. They were simply willing to follow the data where it led, and to listen when a colleague suggested a new direction. Sometimes that is how breakthroughs happen.
Notable Quotes
What's exciting about N-PPG is that it has a dual mechanism of action—it not only inhibits the key enzyme in the pathway that generates oxalate, but it also induces mitohormesis, a beneficial stress response that strengthens mitochondrial resilience.— Lisa Ellerby, neuroscientist at Buck Institute
It's a fun collaboration and it shows what can happen when your next-door neighbor is open and receptive.— Gary Scott, senior scientist at Buck Institute
The Hearth Conversation Another angle on the story
How did two researchers studying completely different diseases end up solving a problem in nephrology?
It was genuinely accidental. Scott was looking at N-PPG as a cancer agent and noticed it seemed to improve cell function through a stress response. He mentioned it to Ellerby, who works next door, and she asked if it might help with Huntington's disease. When it did, they started asking why—and discovered the molecule was affecting the oxalate pathway.
So they weren't hunting for a kidney stone treatment at all.
Not at all. They were following a metabolic thread that appeared when they looked closely at what N-PPG was actually doing inside cells. That curiosity led them somewhere neither expected to go.
The survival difference in the mice is remarkable—15 weeks versus 24 weeks. But what does that really mean for a patient?
It means the difference between a disease that kills you in childhood or early adulthood and one that doesn't. Right now, PH2 patients have no options. They get kidney stones, progressive kidney damage, and eventually need transplants just to survive. This molecule appears to stop that cascade entirely.
You mentioned N-PPG has a dual mechanism—blocking an enzyme and triggering mitohormesis. Why does that matter?
Because it's not just removing the poison. It's also making the kidney stronger and more resistant to damage. That's why the treated mice looked completely normal, not just less sick. They had both reduced oxalate and more resilient tissues.
What happens next?
More safety studies in animals, then eventually human trials if everything checks out. But the researchers are also developing related compounds to understand which parts of N-PPG's action produce the kidney benefits. They're not stopping at one molecule.