Abstract
Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which catalyzes conversion of glyoxylate into glycine. AGT deficiency results in overproduction of oxalate that ultimately leads to end-stage renal disease and death. Organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation is the only available therapy to prevent disease progression. Gene therapy is an attractive option to provide an alternative treatment for PH1. Toward this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. Compared with saline controls, AGT-deficient mice injected with an HDAd encoding the AGT under the control of a liver-specific promoter showed a significant reduction of hyperoxaluria and less increase of urinary oxalate following challenge with ethylene glycol, a precursor of glyoxylate. These studies may thus pave the way to clinical application of HDAd for PH1 gene therapy.
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Acknowledgements
We thank Dr Roy-Chowdhury for providing us Agxt−/− mice and Dr Elisa Oppici for the anti-AGT antibody. We thank TIGEM Bioinformatic core for statistical analyses and the staff of TIGEM/IGB animal facility for assistance with mouse procedures. RC was supported by PONa3_00311. This work was supported by research grants of The Hyperoxaluria and Oxalosis Foundation to NB-P and Fondazione Telethon, Italy (TCBP37TELC and TCBMT3TELD to NB-P).
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Castello, R., Borzone, R., D'Aria, S. et al. Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther 23, 129–134 (2016). https://doi.org/10.1038/gt.2015.107
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DOI: https://doi.org/10.1038/gt.2015.107