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Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector.


ABSTRACT: Neonatal gene therapy has the potential to ameliorate abnormalities before disease onset. Our gene knockout of arginase I (AI) deficiency is characterized by increasing hyperammonemia, neurological deterioration, and early death. We constructed a helper-dependent adenoviral vector (HDV) carrying AI and examined for correction of this defect. Neonates were administered 5 x 10(9) viral particles/g and analyzed for survival, arginase activity, and ammonia and amino acids levels. The life expectancy of arg(-/-) mice increased to 27 days while controls died at 14 days with hyperammonemia and in extremis. Death correlated with a decrease in viral DNA/RNA per cell as liver mass increased. Arginase assays demonstrated that vector-injected hepatocytes had ~20% activity of heterozygotes at 2 weeks of age. Hepatic arginine and ornithine in treated mice were similar to those of saline-injected heterozygotes at 2 weeks, whereas ammonia was normal. By 26 days, arginase activity in the treated arg(-/-) livers declined to <10%, and arginine and ornithine increased. Ammonia levels began increasing by day 25, suggesting the cause of death to be similar to that of uninjected arg(-/-) mice, albeit at a later time. These studies demonstrate that the AI deficient newborn mouse can be temporarily corrected and rescued using a HDV.

SUBMITTER: Gau CL 

PROVIDER: S-EPMC2835205 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector.

Gau Chia-Ling CL   Rosenblatt Robin A RA   Cerullo Vincenzo V   Lay Fides D FD   Dow Adrienne C AC   Livesay Justin J   Brunetti-Pierri Nicola N   Lee Brendan B   Cederbaum Stephen D SD   Grody Wayne W WW   Lipshutz Gerald S GS  

Molecular therapy : the journal of the American Society of Gene Therapy 20090414 7


Neonatal gene therapy has the potential to ameliorate abnormalities before disease onset. Our gene knockout of arginase I (AI) deficiency is characterized by increasing hyperammonemia, neurological deterioration, and early death. We constructed a helper-dependent adenoviral vector (HDV) carrying AI and examined for correction of this defect. Neonates were administered 5 x 10(9) viral particles/g and analyzed for survival, arginase activity, and ammonia and amino acids levels. The life expectancy  ...[more]

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