title: Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1.
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.
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Castello
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Borzone
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: D'Aria
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Annunziata
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: P
authors.identifier: http://orcid.org/0000-0002-8614-2581
authors.initials: P
authors.lastname: Piccolo
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.|Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Brunetti-Pierri
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000628:therapy*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D000637:Transaminases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000637:Transaminases; C023067:glyoxylate aminotransferase