Not just reducing the poison — toughening the tissue that has to survive it.
There are roughly 1,700 people in the United States living with Primary Hyperoxaluria Type 2, a rare inherited disorder that turns the body against its own kidneys. Many more cases almost certainly go undiagnosed. For all of them, there is currently no treatment — only the slow accumulation of calcium oxalate crystals in the kidneys, recurrent stone attacks, progressive organ damage, and, for the most severe cases, the grim arithmetic of transplant lists. That may be about to change.
Researchers at the Buck Institute for Research on Aging in Novato, California, have published findings in the journal Kidney International showing that a small, orally administered molecule called N-propargylglycine — N-PPG — can completely prevent kidney stone formation, protect kidney function, and fully restore normal survival in mice engineered to carry the PH2 disease. In a six-month survival study, untreated PH2 mice on a hydroxyproline-rich diet — designed to replicate the metabolic conditions of the human disease — had a median survival of just 15 weeks, with nearly all dying of renal failure. Mice given daily oral doses of N-PPG survived the entire 24-week study period, their weight, kidney function, and survival rates indistinguishable from healthy controls.
The disease belongs to a family of rare metabolic disorders called primary hyperoxalurias, in which the body overproduces oxalate, a compound that at elevated concentrations crystallizes in the kidneys. The most common form, PH Type 1, now has two RNA-based therapies that offer partial relief. PH2 and PH3 patients have nothing. Many eventually face combined kidney and liver transplantation simply to stay alive.
N-PPG works by blocking an enzyme called hydroxyproline dehydrogenase — known as HYPDH or PRODH2 — that sits inside the mitochondria of liver and kidney cells. This enzyme initiates the breakdown of hydroxyproline, an amino acid released during normal collagen turnover. In healthy people, the downstream metabolite glyoxylate is safely processed. In PH2 patients, a genetic defect means glyoxylate instead converts to oxalate in excess quantities. By shutting off the pathway at its first step, N-PPG cuts off the excess oxalate supply before it can do damage.
But the molecule does something else, too — something the researchers find equally compelling. N-PPG also triggers a cellular process called mitohormesis, in which a mild, controlled stress on the mitochondria prompts the cell to strengthen its own defenses. As Lisa Ellerby, a Buck Institute professor who studies Huntington's and Alzheimer's disease, put it, the compound isn't just reducing the toxic burden of oxalate; it's also making the kidney more resilient to whatever damage oxalate might still cause. That dual mechanism sets N-PPG apart from a simple enzyme inhibitor.
The path to this discovery was not a straight line. It began with a hallway conversation. Gary Scott, a senior scientist in the Benz lab who was investigating N-PPG as a potential anti-cancer agent, happened to mention his results to Ellerby, whose lab occupied adjacent space. Scott described how the molecule improved normal cell function through mitohormesis. Ellerby suggested testing it in a cell model of Huntington's disease. It corrected roughly half the gene expression changes associated with that condition. As the two teams dug into the underlying metabolic picture, they noticed N-PPG's involvement in the oxalate-producing pathway — and a collaboration that had started in oncology and neuroscience pivoted, unexpectedly, into nephrology.
"We became quite excited about that," Scott said of the kidney stone connection. Christopher Benz, the Buck professor and oncologist who leads the lab where Scott works, put it plainly: the data and the excitement led them somewhere none of them had anticipated going.
The early results are striking enough that the researchers believe N-PPG's reach may extend beyond PH2. Because both PH2 and PH3 share the same hydroxyproline breakdown pathway in the liver, the molecule could eventually prove useful across both subtypes. And because calcium oxalate kidney stones are among the most common urological complaints in the general population, the mitohormetic properties of N-PPG might one day offer something to patients far beyond the rare disease community.
For now, the molecule has shown good tolerability across multiple mouse studies lasting up to six months, with no significant effects on health, activity, body weight, or organ function. But the researchers are clear-eyed about what remains: pharmacokinetic studies, formal safety evaluations, and the long road of clinical development still lie ahead. Additional chemical analogs are also being developed to better understand which of N-PPG's two mechanisms — enzyme inhibition or mitohormesis — is doing more of the protective work. Studies in PH3 animal models are planned once better models become available. The molecule is not yet a drug. But for a disease with no options at all, it is, at minimum, a door that has just opened.
Notable Quotes
It not only inhibits a key enzyme in the pathway that generates oxalate, but it also induces mitohormesis — a beneficial stress response that strengthens mitochondrial resilience.— Lisa Ellerby, PhD, Professor, Buck Institute for Research on Aging
That's where the data and excitement led us. It really attests to a unique quality at the Buck — collaborative and interdisciplinary research not typically found within academic universities and larger institutes.— Christopher Benz, MD, Professor, Buck Institute for Research on Aging
The Hearth Conversation Another angle on the story
Why does this particular disease have no treatments when other forms of the same condition do?
The most common form, PH1, got RNA-based therapies first because it affects more people and the target enzyme was easier to reach. PH2 and PH3 are rarer, the biology is different, and the field simply hadn't found a viable molecular handle — until now.
What makes N-PPG different from just blocking the enzyme directly?
Most inhibitors do one thing. N-PPG does two. It cuts off the oxalate supply at the source, but it also triggers mitohormesis — a kind of controlled stress that makes the kidney's own cells more durable. You're not just reducing the poison; you're toughening the tissue that has to survive it.
How did a cancer researcher and a neurologist end up solving a kidney disease?
They shared lab space and talked to each other. Scott was studying N-PPG as an anti-cancer agent. Ellerby suggested trying it in Huntington's disease models. When they traced the metabolic pathway, they found oxalate sitting right in the middle of it. The kidney stone connection was a surprise to everyone.
The survival numbers in the mouse study are pretty dramatic. Is that unusual?
It's rare to see complete survival restoration in a disease model this severe. The untreated mice were dying at a median of 15 weeks. The treated mice lived the full 24 weeks of the study, looking essentially normal. That kind of result tends to get people's attention.
What's the biggest obstacle between this and a human treatment?
The usual ones — pharmacokinetics, formal safety studies, clinical trials. The molecule has been well-tolerated in mice for up to six months, but that's a long way from a human drug. The researchers are also still trying to understand which of its two mechanisms matters more, which will shape how they develop it.
Could this ever help people who just get ordinary kidney stones, not the genetic kind?
That's exactly what the researchers are wondering. Calcium oxalate stones are extremely common. If the mitohormetic effect strengthens kidney resilience broadly, N-PPG might have a role well beyond rare disease — though that's still speculative at this stage.