Danica Grujić1, Eduardo Salido2, Bhami C. Shenoy1, Craig B. Langman3, Margaret E. McGrath1, Reena Patel1, Aftab Rashid1, Saraswathi Mandapati1, Chu W. Jung1, Alexey L. Margolin1
1Altus Pharmaceuticals, Cambridge, Mass., USA
2Unidad Investigacion, Hospital Universitario de Canarias, CIBERER, La Laguna, Tenerife, Spain
3Feinberg School of Medicine, Northwestern University, Children's Memorial Hospital, Chicago, Ill., USA
Tóm tắt
<i>Background/Aims:</i> Hyperoxaluria is a major risk factor for recurrent urolithiasis and nephrocalcinosis. We tested an oral therapy with a crystalline, cross-linked formulation of oxalate-decarboxylase (OxDc-CLEC®) on the reduction of urinary oxalate and decrease in the severity of kidney injury in two models: AGT1 knockout mice (AGT1KO) in which hyperoxaluria is the result of an <i>Agxt</i> gene deficiency, and in AGT1KO mice challenged with ethylene glycol (EG). <i>Methods:</i> Four different doses of OxDc-CLEC mixed with the food, or placebo were given to AGT1KO mice (200 mg/day, n = 7) for 16 days and to EG-AGT1KO mice (5, 25, and 80 mg, n = 11) for 32 days. <i>Results:</i> Oral therapy with 200 mg OxDc-CLEC reduced both urinary (44%) and fecal oxalate (72%) in AGT1KO mice when compared to controls. Similarly, in EG-AGT1KO mice, each of the three doses of OxDc-CLEC produced a 30–50% reduction in hyperoxaluria. A sustained urinary oxalate reduction of 40% or more in the 80 mg group led to 100% animal survival and complete prevention of nephrocalcinosis and urolithiasis. <i>Conclusion:</i> These data suggest that oral therapy with OxDc-CLEC may reduce hyperoxaluria, prevent calcium oxalate nephrocalcinosis and urolithiasis, and can represent a realistic option for the treatment of human hyperoxaluria, independent of cause.
