Scientists at the Buck Institute for Research on Aging have shown that an orally administered small molecule,\u00a0N-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), \u00a0a rare and currently untreatable genetic disorder that causes progressive kidney failure in infants and young adults. \u00a0An estimated 1,700 people suffer from the disease in the US, although experts believe many more cases go undiagnosed.<\/p>\n
The findings, published in\u00a0Kidney International<\/a>, are the result of a unique collaboration between Buck Institute scientists studying breast cancer and Huntington\u2019s disease. The discovery represents a significant step toward a much-needed therapy for patients with PH2, a lethal inborn error of a metabolic disease without any available treatments.<\/p>\n Primary hyperoxaluria is a group of rare inherited metabolic disorders in which the body overproduces oxalate, a compound that, at high levels, forms calcium oxalate crystals in the kidneys. These crystals cause recurrent kidney stones, progressive kidney damage, and in severe cases, end-stage kidney failure. While the most common form of the disease, PH Type 1, now has two approved RNA-based therapies that are partially effective, patients with PH2 and PH3 have no therapeutic options and often face kidney and liver transplantation in an effort to extend their survival.<\/p>\n The Buck team\u2019s approach targets a key enzyme called hydroxyproline dehydrogenase (HYPDH\/PRODH2), that resides in liver and kidney mitochondria and catalyzes the first step in breaking down hydroxyproline, an amino acid derived largely from collagen turnover. This breakdown pathway generates glyoxylate, which in PH2 patients is not properly metabolized and instead produces excess amounts of oxalate. By blocking HYPDH\/PRODH2 with\u00a0N-PPG, the researchers were able to cut off the excess oxalate production at its source, preventing its damaging precipitation as calcium oxalate (CaOx) kidney stones.<\/p>\n The story behind the research<\/p>\n The findings stem from a serendipitous conversation between researchers studying different age-related diseases while sharing common lab space. \u00a0Gary Scott, PhD, a senior scientist studying breast cancer in the Benz lab, was chatting with Professor Lisa Ellerby PhD, a neuroscientist who studies Huntington\u2019s and Alzheimer\u2019s disease. At that point Scott was looking at\u00a0N-PPG as a potential anti-mitochondrial cancer agent. When discussing the results with Ellerby, Scott mentioned that\u00a0N-PPG improved functioning in normal cells via a response known as mitohormesis, whereby a small amount of stress in the mitochondria improves the cell\u2019s functioning.<\/p>\n Ellerby said her lab had been thinking about how mitohormesis impacts neurological disease and suggested that they test\u00a0N-PPG on a cell model of Huntington\u2019s disease.\u00a0N-PPG corrected about 50% of the gene expression changes that accompany the hereditary neurological disease. The two teams dug deeper into what was occurring metabolically and discovered that\u00a0N-PPG was involved in the pathway that produces oxalate; at that point the two teams started looking at kidney stones. \u201cWe became quite excited about that, generating our interest in a completely different field: nephrology,\u201d says Scott. \u201cIt\u2019s a fun collaboration and it shows what can happen when your next-door neighbor is open and receptive the way Lisa is.\u201d<\/p>\n Results<\/p>\n In an initial three-week study,\u00a0N-PPG treatment significantly reduced urinary oxalate levels and nearly eliminated calcium oxalate stone formation in mice with PH2. Treated mice also showed markedly less kidney tubule damage and better-preserved kidney function compared to untreated animals, which rapidly developed stone-laden, injured kidneys.<\/p>\n In a landmark six-month survival study, the results were even more striking. Untreated PH2 mice on a hydroxyproline-rich diet, designed to mimic the human disease, had a median survival of only 15 weeks, with nearly all mice dying of renal failure. However, the PH2 mice treated daily with oral\u00a0N-PPG survived the full 24 weeks of the study, with survival, weight, and kidney function indistinguishable from normal healthy wild-type controls. Both senior scientists think the results could have major impact on kidney disease, something they never anticipated.<\/p>\n \u201cWhat\u2019s exciting about\u00a0N-PPG is that it has a dual mechanism of action,\u201d says Ellerby. \u201cIt 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\u2019re not just reducing the toxic oxalate burden; we\u2019re also making the kidney more resilient to any damage it might cause.\u201d<\/p>\n The researchers note that because both PH2 and PH3 depend on the same hydroxyproline catabolism liver pathway to generate excess oxalate,\u00a0N-PPG may ultimately have therapeutic potential across both subtypes of this inherited disease. Future studies are planned to evaluate\u00a0N-PPG in PH3 models once improved animal models become available.<\/p>\n N-PPG has previously demonstrated good tolerability in multiple mouse model studies where it\u2019s been administered for up to six months, showing no significant adverse effects on health, activity, body weight, or organ function. The authors note that further 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\u00a0N-PPG relative to simply reducing liver oxalate production with a selective HYHPDH\/PRODH2 inhibitor.\u00a0\u00a0<\/p>\n Ellerby is thrilled by this additional new direction in her lab, as she works on rare \u201corphan\u201d neurological diseases that affect only a small number of people. Benz, who is an oncologist, says he never envisioned going in the direction of neurodegeneration or kidney stones but \u201cThat\u2019s where the data and excitement led us,\u201d he says.\u00a0 \u201cIt really attests to a unique quality at the Buck; collaborative and interdisciplinary research, not typically found within academic universities and larger institutes.\u201d<\/p>\n Reference:\u00a0Hady M, Tadeo A, Stoyanova D, et al. N-propargylglycine restores survival by preventing calcium oxalate stone formation, tubular injury, and kidney dysfunction in a lethal mouse model of primary hyperoxaluria type 2. Kidney Int. 2026:S0085253826002188. doi:\u00a010.1016\/j.kint.2026.02.024<\/a><\/p>\n This article has been republished from the following materials<\/a>. Note: material may have been edited for length and content. For further information, please contact the cited source. 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