Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper-dependent adenoviral vectors.
BACKGROUND
Helper-dependent adenoviral vectors (HDAd) can mediate long-term phenotypic correction in the ornithine transacarbamylase (OTC)-deficient mice model with negligible chronic toxicity. However, the high doses required for metabolic correction will result in systemic inflammatory response syndrome in humans. This acute toxicity represents the major obstacle for clinical applications of HDAd vectors for the treatment of OTC deficiency. Strategies for reducing the dose necessary for disease correction are highly desirable because HDAd acute toxicity is clearly dose-dependent.


METHODS
We analysed a potent expression cassette and the hydrodynamic injection for the ability to reduce the HDAd dose necessary for phenotypic correction in OTC-deficient spf-ash mice.


RESULTS
We have developed a vector containing a potent expression cassette expressing the OTC transgene, which allowed phenotypic correction at lower doses. Our results suggest that vector expressing greater OTC levels allows correction of orotic acid overproduction at lower doses that make clinical translation more relevant. We were able to further reduce the minimal effective dose by delivering the vector through the hydrodynamic injection technique.


CONCLUSIONS
Vectors containing the expression cassette used in the present study, combined with other strategies for improving HDAd therapeutic index, will likely permit application of these vectors for the treatment of OTC deficiency as well as other urea cycle disorders.
Brunetti-Pierri
Nicola
N
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Clarke
Christian
C
Mane
Viraj
V
Palmer
Donna J
DJ
Lanpher
Brendan
B
Sun
Qin
Q
O'Brien
William
W
Lee
Brendan
B
D000256:Adenoviridae / Q000235:genetics*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000628:therapy*; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D006651:Histocytochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009954:Ornithine Carbamoyltransferase / Q000235:genetics* / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D009963:Orotic Acid / Q000652:urine; D019076:Transgenes
D009963:Orotic Acid; D009954:Ornithine Carbamoyltransferase