703. Liver-Directed Gene Therapy for Primary Hyperoxaluria Type 1

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 converted into glycine and is oxidized to oxalate resulting in hyperoxaluria. The excess of oxalate causes deposition of insoluble calcium oxalate in the kidney and other tissues leading to nephrolithiasis, nephrocalcinosis, kidney failure, and systemic tissue damage. Combined liver/kidney transplantation is the only available therapeutic strategy for disease treatment. Gene therapy is an attractive option to provide a definitive cure for PH1. Towards this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. We injected PH1 mice with an HDAd encoding AGT under the control of a liver-specific promoter and observed normalization of urinary oxalate at the doses of 5×10e12 and 1×10e13 vector particles (vp)/kg and partial correction with 1×10e12 vp/kg. Following challenge with Ethylene Glycol (EG), a precursor of glyoxylate, we observed reduced elevations of urinary oxalate in HDAd-injected mice compared to saline controls.Next, we hypothesized that overexpression of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) or glutamate-pyruvate transaminase (GPT) results in reduction of hyperoxaluria in PH1 by steering glyoxylate towards glycolate synthesis or transamination, respectively. To test this hypothesis, we injected PH1 mice with HDAd vectors expressing GRHPR or GPT. Both vectors resulted in significant reduction of hyperoxaluria and co-injection of the two vectors resulted in long-term normalization of oxalate excretion. Therefore, metabolic diversion towards non-toxic metabolites has potential for treatment of hyperoxaluria and vector-mediated GRHPR and/or GPT overexpression may be an alternative or adjunctive strategy to enhance efficiency of gene replacement therapy for PH1.We have recently developed a minimally invasive method to improve the therapeutic index of HDAd based on balloon occlusion catheter to achieve preferential delivery of the vector to the liver (Brunetti-Pierri et al., 2009 and 2012). This method may permit in humans correction of PH1 using clinically relevant lower doses of HDAd. Based on risk:benefit assessment, PH1 is an attractive disease for clinical application of this method.