Hyperoxaluria is reduced and nephrocalcinosis prevented with an oxalate-degrading enzyme in mice with hyperoxaluria.
OBJECTIVE
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 Agxt gene deficiency, and in AGT1KO mice challenged with ethylene glycol (EG).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Grujic
Danica
D
Altus Pharmaceuticals, 625 Putnam Avenue, Cambridge, MA 02139, USA. dgrujic@altus.com
Salido
Eduardo C
EC
Shenoy
Bhami C
BC
Langman
Craig B
CB
McGrath
Margaret E
ME
Patel
Reena J
RJ
Rashid
Aftab
A
Mandapati
Saraswathi
S
Jung
Chu W
CW
Margolin
Alexey L
AL
D000284:Administration, Oral; D026905:Amino Acid Transport Systems / Q000235:genetics; D000818:Animals; D002262:Carboxy-Lyases / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004195:Disease Models, Animal; D019855:Ethylene Glycol / Q000633:toxicity; D005243:Feces; D006959:Hyperoxaluria / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009397:Nephrocalcinosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010070:Oxalates / Q000652:urine*; D010447:Peptide Hydrolases / Q000378:metabolism; D052878:Urolithiasis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control
D026905:Amino Acid Transport Systems; D010070:Oxalates; C459184:Slc7a13 protein, mouse; D010447:Peptide Hydrolases; D002262:Carboxy-Lyases; C021915:oxalate decarboxylase; D019855:Ethylene Glycol