Breakthrough Research Identifies Oral Drug Candidate for Rare Kidney Disease

Scientists at the Buck Institute for Research on Aging have identified N-propargylglycine (N-PPG), an orally administered small molecule, that demonstrated the ability to prevent calcium oxalate kidney stone formation, protect against kidney failure, and restore normal survival in a mouse model of Primary Hyperoxaluria Type 2 (PH2). PH2 is a rare, inherited metabolic disorder that currently lacks specific treatments and can lead to progressive kidney failure in affected individuals.

Primary Hyperoxaluria Type 2 (PH2) is a rare, inherited metabolic disorder that currently lacks specific treatments and can lead to progressive kidney failure. Approximately 1,700 individuals in the U.S. are estimated to have PH2, with potentially more cases undiagnosed.

Understanding Primary Hyperoxaluria

Primary hyperoxaluria (PH) refers to a group of inherited metabolic disorders characterized by the body's overproduction of oxalate. Elevated oxalate levels result in the formation of calcium oxalate crystals, primarily in the kidneys, leading to recurrent kidney stones, progressive kidney damage, and, in severe cases, end-stage kidney failure.

While Primary Hyperoxaluria Type 1 (PH1) has access to two partially effective RNA-based therapies, patients diagnosed with PH2 and PH3 currently do not have approved therapeutic options. This often necessitates kidney and liver transplantation for affected individuals.

Mechanism of Action

The research, published in Kidney International, focuses on the enzyme hydroxyproline dehydrogenase (HYPDH/PRODH2), located in the mitochondria of liver and kidney cells. This enzyme initiates the breakdown of hydroxyproline, an amino acid, a process that generates glyoxylate. In individuals with PH2, glyoxylate is not properly metabolized, leading to an excessive production of oxalate.

N-PPG works by blocking HYPDH/PRODH2, thereby interrupting the source of excess oxalate and preventing the formation of calcium oxalate kidney stones.

N-PPG also exhibits a dual mechanism of action by inducing mitohormesis. This beneficial stress response enhances mitochondrial resilience, contributing to reducing the toxic oxalate burden and potentially strengthening the kidney's ability to resist damage.

From Cancer to Kidney Stones: The Discovery of N-PPG

The discovery of N-PPG's potential for PH2 originated from an interdisciplinary collaboration between scientists at the Buck Institute. Dr. Gary Scott, initially researching breast cancer, observed that N-PPG improved cell functioning through mitohormesis as a potential anti-mitochondrial cancer agent.

A discussion with Dr. Lisa Ellerby, a neuroscientist studying Huntington's disease, led to testing N-PPG on a Huntington's disease cell model, where it reportedly corrected approximately 50% of associated gene expression changes. Further metabolic investigations subsequently revealed N-PPG's involvement in the oxalate production pathway, leading the research focus to nephrology and kidney stones.

Study Findings

In an initial three-week study involving PH2 mice:

• N-PPG treatment reduced urinary oxalate levels.
• Calcium oxalate stone formation was nearly eliminated.
• Treated mice exhibited reduced kidney tubule damage.
• Kidney function in treated mice was better preserved compared to untreated animals, which developed stone-laden and injured kidneys.

A subsequent six-month survival study provided further data:

• Untreated PH2 mice, maintained on a hydroxyproline-rich diet to mimic the human disease, had a median survival of 15 weeks, primarily due to renal failure.
• PH2 mice treated daily with oral N-PPG survived the entire 24-week study period.
• Survival, body weight, and kidney function in the treated PH2 mice were comparable to those of normal healthy control mice.

Safety and Future Outlook

N-PPG has shown tolerability in multiple mouse model studies over six months, with no significant adverse effects reported on health, activity, body weight, or organ function.

Researchers indicate N-PPG's potential therapeutic application for PH3, given that both PH2 and PH3 involve the same hydroxyproline catabolism pathway for excess oxalate generation. Its mitohormetic properties may also extend its utility to preventing more common forms of recurrent calcium oxalate kidney stone disease and other organ disorders that could benefit from enhanced mitochondrial resistance.

Further pharmacokinetic and safety studies are required before N-PPG can advance to clinical development. Additionally, researchers are developing chemical analogs to further differentiate and understand the kidney mitohormesis benefits of N-PPG from its direct reduction of liver oxalate production. Studies evaluating N-PPG in PH3 models are also planned.