Primary hyperoxaluria type I (PH1) is caused by the absence, deficiency or mistargeting of the liver-specific peroxisomal alanine-glyoxylate aminotransferase (AGT), which provides the final step of glyoxylate detoxification. In the absence of peroxisomal AGT, glyoxylate diffuses into the cytosol, where it is converted to oxalate by lactate dehydrogenase. Due to the low solubility of calcium oxalate, peroxisomal AGT deficiency results in kidney stone formation, progressive nephrocalcinosis, decline in kidney function to ESRD and subsequent systemic deposition of calcium oxalate crystals. Currently, the only curative option in treating children with PH1 who progress to ESRD, is combined liver-kidney transplantation.
The presentation will discuss various novel therapeutic approaches including: 1. Gene therapy. 2. Re-routing of the mis-targeted AGT from the mitochondria into the peroxisome by mild translation elongation inhibition and rescuing its enzymatic activity in CHO cells. 3. A clinical study using substrate reduction by siRNA directed to HAO1 encoding glycolate reductase (GO), the enzyme that catalyzes the production of glyoxylate, the immediate precursor of oxalate.