Gene therapy and Primary hyperoxaluria type 1

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Primary hyperoxaluria type 1 (PH1) is a condition caused by a deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). PH1 is estimated to account for about 1% of pediatric cases of end-stage renal failure and to occur in 1:120,000 live births in Europe. It typically presents with renal colic or asymptomatic gross hematuria before the age of 5 years. Almost half of patients present with end-stage renal disease at the time of diagnosis.

Liver transplantation or combined liver/kidney transplantation are the only available therapeutic modalities to prevent disease progression. Castello et al. recently explored helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1 in AGT-deficient mice.

A significant reduction of hyperoxaluria was reported in mice injected with an HDAd encoding the AGT (under the control of a liver-specific promoter) when compared with control mice injected with saline. AGT catalyzes the reaction of glyoxylate into glycine. Ethylene glycol is a precursor of glyoxylate. A challenge of the two groups of mice with ethylene glycol showed that the mice having been treated with gene therapy showed less increase of urinary oxalate, providing further evidence that the treatment has had a significant impact.

For more information on primary hyperoxaluria, you can refer to chapter 133 of OMMBID.

Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Castello R, Borzone R, D’Aria S, Annunziata P, Piccolo P, Brunetti-Pierri N. Gene Ther. 2015 Dec 24. doi: 10.1038/gt.2015.107. [Epub ahead of print] PMID: 26609667

Posted by Yannis Trakadis, MD

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