Introduction: New therapeutics are needed to address the rapid progression of calcium oxalate (CaOx) nephrolithiasis and life-threatening kidney failure afflicting infants and young adults with one of the three different genetic types of Primary Hyperoxaluria (PH) types 1, 2, and 3. Glyoxylate and hydroxypyruvate reductase knockout (Grhpr KO) mice recapitulate the pathophysiology of PH type 2 (PH2), developing accelerated hyperoxaluria and CaOx kidney stone formation.Previous studies have shown that this process can be mitigated by introducing an additional genetic knockout of the liver and kidney mitochondrial enzyme, hydroxyproline dehydrogenase (Hypdh/Prodh2), which is responsible for the first step in liver production of glyoxylate and oxalate.Methods: Using Grhpr KO mice, we evaluated N-propargylglycine (N-PPG) as a preclinical candidate for PH2, measuring oxalate levels, CaOx stone formation, Cystatin C levels, albumin/creatinine ratio, kidney tubule damage by kidney injury molecule-1 and Lotus Tetragonolobus lectin immunohistochemistry, metabolites, weight, and lifespan.Results: Oral administration of N-PPG, a well-tolerated small-molecule inhibitor of Hypdh/Prodh2, significantly reduces hyperoxaluria and weight loss in Grhpr KO mice within three weeks, while preventing CaOx stone formation and kidney tubular damage.In a 24-week survival study during which vehicle-treated Grhpr KO mice exhibit a median survival of only 15 weeks, daily treatment with N-PPG fully restores weight and survival in the Grhpr KO mice to that of wild-type control mice.N-PPG suppressed hyperoxaluria during this extended treatment period, preventing CaOx stone formation, kidney tubule injury and loss of kidney function, achieving beneficial outcomes in this PH2 mouse model comparable to controls. Conclusions:Our findings establish N-PPG as a promising therapeutic candidate for the longterm prevention of CaOx kidney stone formation and kidney failure complications in PH2.
Hady et al. (2026) studied this question.