Oral Drug N-PPG Shows Complete Prevention of Kidney Stones and Death in Rare Disease Model
核心洞察
Scientists at the Buck Institute for Research on Aging have demonstrated that an oral small molecule, N-propargylglycine (搜索) (N-PPG (搜索)), completely prevents calcium oxalate kidney stone formation and restores normal survival in mice with Primary Hyperoxaluria Type 2 (搜索) (PH2 (搜索)).
The drug works by blocking the enzyme HYPDH/PRODH2 (搜索) that drives excess oxalate production while also strengthening mitochondrial resilience through a process called mitohormesis.
In six-month survival studies, untreated PH2 (搜索) mice died by 15 weeks from kidney failure (搜索), while N-PPG (搜索)-treated mice survived the full 24-week study period with normal kidney function.
Scientists at the Buck Institute for Research on Aging have achieved a breakthrough in treating Primary Hyperoxaluria Type 2 (搜索) (PH2 (搜索)), demonstrating that an oral small molecule called N-propargylglycine (搜索) (N-PPG (搜索)) can completely prevent kidney stone formation and restore normal survival in a mouse model of this rare, lethal genetic disorder. The findings, published in Kidney International, represent the first potential therapeutic option for patients with PH2, who currently face kidney and liver transplantation as their only survival strategy.
Addressing an Unmet Medical Need
Primary Hyperoxaluria Type 2 (搜索) is a rare inherited metabolic disorder affecting an estimated 1,700 people in the United States, though experts believe many cases remain undiagnosed. The condition causes the body to overproduce oxalate, leading to calcium oxalate crystal formation in the kidneys. These crystals cause recurrent kidney stones (搜索), progressive kidney damage, and ultimately end-stage kidney failure (搜索) in infants and young adults.
While the most common form, PH Type 1, now has two approved RNA-based therapies that are partially effective, patients with PH2 (搜索) and PH3 have no therapeutic options. Progression to kidney failure (搜索) occurs in 25% to 35% of patients, typically requiring transplantation for survival.
Dual Mechanism of Action
The Buck Institute team's approach targets hydroxyproline dehydrogenase (搜索) (HYPDH/PRODH2 (搜索)), a key enzyme in liver and kidney mitochondria that catalyzes the breakdown of hydroxyproline, an amino acid derived largely from collagen turnover. This breakdown pathway generates glyoxylate, which in PH2 (搜索) patients is not properly metabolized and instead produces excess oxalate.
"What's exciting about N-PPG (搜索) is that it has a dual mechanism of action," explains Professor Lisa Ellerby, PhD, one of the study's senior authors. "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."
Striking Survival Results
In initial three-week studies, N-PPG (搜索) treatment significantly reduced urinary oxalate levels and nearly eliminated calcium oxalate stone formation in PH2 (搜索) mice. Treated animals showed markedly less kidney tubule damage and better-preserved kidney function compared to untreated controls, which rapidly developed stone-laden, injured kidneys.
The six-month survival study produced even more dramatic results. Untreated PH2 (搜索) mice on a hydroxyproline-rich diet designed to mimic human disease had a median survival of only 15 weeks, with nearly all mice dying of renal failure. In stark contrast, PH2 mice treated daily with oral N-PPG (搜索) survived the full 24 weeks of the study, with survival, weight, and kidney function indistinguishable from normal healthy controls.
Serendipitous Discovery
The breakthrough emerged from an unexpected collaboration between researchers studying different age-related diseases. Gary Scott, PhD, a senior scientist studying breast cancer (搜索), was initially investigating N-PPG (搜索) as a potential anti-mitochondrial cancer agent when he discussed his findings with neuroscientist Professor Ellerby, who studies Huntington's and Alzheimer's disease (搜索).
"We became quite excited about that, generating our interest in a completely different field: nephrology. It's a fun collaboration and it shows what can happen when your next-door neighbor is open and receptive the way Lisa is," Scott noted.
When the teams tested N-PPG (搜索) on a Huntington's disease (搜索) cell model, it corrected about 50% of the gene expression changes associated with the hereditary neurological condition. Further metabolic investigation revealed N-PPG's involvement in the oxalate production pathway, leading to their kidney stone research.
Broader Therapeutic Potential
Buck professor Christopher Benz, MD, emphasized the drug's promising characteristics: "N-PPG (搜索) 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 (搜索) 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 note that because both PH2 (搜索) and PH3 depend on the same hydroxyproline catabolism liver pathway to generate excess oxalate, N-PPG (搜索) may ultimately have therapeutic potential across both subtypes of inherited hyperoxaluria.
Safety Profile and Next Steps
N-PPG (搜索) has demonstrated good tolerability in multiple mouse model studies with administration periods up to six months, showing no significant adverse effects on health, activity, body weight, or organ function. However, the authors acknowledge that further pharmacokinetic and safety studies are needed before advancing to clinical development.
The research team is also developing additional chemical analogs to better understand the kidney mitohormesis benefits of N-PPG (搜索) relative to simply reducing liver oxalate production with selective HYPDH/PRODH2 (搜索) inhibition. Future studies are planned to evaluate N-PPG in PH3 models once improved animal models become available.