title: Adenovirus-mediated in vivo gene transfer rapidly protects ornithine transcarbamylase-deficient mice from an ammonium challenge.
abstract: The purpose of this study was to determine the time of onset, duration, and the efficacy of in vivo gene transfer in protecting the ornithine transcarbamylase deficient spf/Y mouse from an acute ammonium challenge. The animals were challenged with ammonia (10 mmol/kg NH4Cl) 1, 2, 7, 14, or 28 d after the administration of a recombinant adenoviral construct deleted in E1 and with a temperature sensitive mutation in E2. Although there was no protection with the control LacZ virus, the ornithine transcarbamylase (OTC)-containing vector provided partial protection from both behavioral symptoms (ataxia, seizures, and abnormal response to sound) and biochemical abnormalities (ammonium, aspartate, alanine, and glutamine) within 24 h and complete protection by 48 h. Mortality was also decreased. Animals receiving the vector 7 and 14 d before the ammonium load were also protected, whereas those treated 28 d before the challenge were not. OTC enzyme activity in liver of untreated spf/Y mice was 5% of control C3H mice. After gene transfer, activity was increased to near control levels through 14 d but had returned to baseline by 28 d. These studies indicate that adenovirus-mediated gene transfer confers a metabolic benefit within 24 h of administration and provides protection against an acute metabolic insult for at least 2 wk.
authors.affiliation: Institute for Human Gene Therapy, University of Pennsylvania Health System, Philadelphia, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ye
authors.forename: M B
authors.initials: MB
authors.lastname: Robinson
authors.forename: C
authors.initials: C
authors.lastname: Pabin
authors.forename: T
authors.initials: T
authors.lastname: Quinn
authors.forename: A
authors.initials: A
authors.lastname: Jawad
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
authors.forename: M L
authors.initials: ML
authors.lastname: Batshaw
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000643:Ammonium Chloride; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007763:Lac Operon; D008099:Liver / Q000201:enzymology; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D009584:Nitrogen / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D013997:Time Factors
chemical_list: D000643:Ammonium Chloride; D009584:Nitrogen