Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector.
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.
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Chia-Ling
CL
Gau
Robin A
RA
Rosenblatt
Vincenzo
V
Cerullo
Fides D
FD
Lay
Adrienne C
AC
Dow
Justin
J
Livesay
Nicola
N
Brunetti-Pierri
Brendan
B
Lee
Stephen D
SD
Cederbaum
Wayne W
WW
Grody
Gerald S
GS
Lipshutz
D000256:Adenoviridae / Q000235:genetics*; D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D022124:Hyperammonemia / Q000628:therapy*; D020162:Hyperargininemia / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout
D000596:Amino Acids; D000641:Ammonia; D001119:Arginase