Metabolic diversion towards non-toxic metabolites for therapy of primary hyperoxaluria type 1. R. Castello1, R. Borzone1, P. Annunziata1, P. Piccolo1, N. Brunetti-Pierri1,2 1) Telethon Institute of Genetics and Medicine, Naples, Italy; 2) Department of Translational Medicine, Federico II University of Naples, Italy.

   Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT) which catalyzes the conversion of glyoxylate to glycine. In PH1 patients, glyoxylate cannot be efficiently converted into glycine and is instead oxidized to oxalate, leading to hyperoxalemia and hyperoxaluria. In turn, this causes the deposition of insoluble calcium oxalate in the kidney and in other tissues, leading to nephrolithiasis, nephrocalcinosis, kidney failure, and systemic tissue damage. Combined liver/kidney transplantation is the only therapeutic strategy available to prevent disease progression. The role of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) in glyoxalate oxidation and oxalate detoxification has been controversial. We hypothesize that GRHPR overexpression results in significant long-term reduction of hyperoxaluria in PH1. To test this hypothesis, we injected Agxt-/- mice with an helper-dependent adenoviral vector expressing murine GRHPR (HDAd-GRHPR) in hepatocytes. The injection of HDAd-GRHPR resulted in significant reduction of hyperoxaluria and concomitant increase of serum glycolate that was not associated with evidence of toxicity. Glutamate-pyruvate transaminase (GPT) in the cytosol efficiently transaminate glyoxylate using L-glutamate and L-alanine as amino-group donors. We hypothesize that GPT overexpression will steer more glyoxylate towards transamination to diminish oxalate production. To test this hypothesis, we injected Agxt-/- mice with a helper-dependent adenoviral vector expressing murine GPT (HDAd-GPT) in hepatocytes. The injection of HDAd-GPT also resulted in significant long-term reduction of hyperoxaluria. In summary, the results of this study show that metabolic diversion towards non-toxic metabolites have potential for treatment of hyperoxaluria. Besides gene transfer, such diversion could be obtained with small molecules increasing GRHPR and/or GPT expression. Moreover, vector-mediated GRHPR or GPT overexpression may be an alternative or adjunctive strategy to ehnance efficiency of gene replacement therapy for PH1. In addition, this approach may be valuable for patients harboring null mutations in the gene encoding AGT which are at increased risk for an immune reaction against the transgene product encoded by vector-transduced cells.

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