Correction of hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type-1.

[primary hyperoxaluria type 1]

Primary hyperoxaluria type -1 (PH 1 ) is an autosomal recessive disease characterized by excessive oxalate production by hepatocytes caused by the deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT ) activity . Persistent hyperoxaluria causes nephrocalcinosis and urolithiasis , leading to renal failure , followed by tissue oxalosis with life-threatening complications . Combined liver -kidney transplantation is the only definitive treatment of PH 1 . Hepatocyte transplantation , which is much less invasive , could have offered an attractive alternative . However , because the AGT -deficient hepatocytes overproduce oxalate , a large fraction of the mutant host hepatocytes must be replaced by AGT -competent cells , which is beyond the capacity of current hepatocyte transplantation procedures . Here , we have evaluated a preparative irradiation-based method of liver repopulation in an Agxt-deleted mouse model of PH 1 (Agxt-/-).Hepatocytes (10 (6 ) viable cells ) isolated from congeneic mice ([ROSA ]26 C 5 7 BL /6 J ) expressing Escherichia coli beta -galactosidase were transplanted into Agxt-/- mice by intrasplenic injection . The preparative regimen consisted of X-irradiation of the host liver and mitotic stimulation of the hepatocytes by adenovector-based expression of hepatocyte growth factor .T he procedure resulted in progressive replacement of the mutant host hepatocytes with the AGT -competent hepatocytes , leading to correction of urinary oxalate excretion . Oral ethylene glycol challenge (0 .7 % for 1 week ) resulted in nephrocalcinosis and microlithiasis in untreated Agxt-/- mice , but not in the mice after hepatic repopulation .The results indicate that hepatocyte transplantation after appropriate preparative regimens may permit sufficient repopulation of the liver to ameliorate hyperoxaluria , and therefore should be evaluated further as a potential treatment of PH 1 .

Diseases
Validation

Diseases presenting "nephrocalcinosis" symptom

cystinuria

familial hypocalciuric hypercalcemia

primary hyperoxaluria type 1

This symptom has already been validated