Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors.
A murine model of ornithine transcarbamylase (OTC) deficiency was used in this study to evaluate the efficacy of recombinant adenoviruses for correcting the metabolic defect in liver. Recombinant adenoviruses deleted in E1 and containing a human OTC cDNA expressed little functional OTC enzyme in vivo and had no observable impact on the underlying metabolic abnormalities of the OTC-deficient mouse (i.e. elevated urinary orotate and serum glutamine). E1-deleted vectors were improved through the use of the strong constitutive promoter from cytomegalovirus driving the normal murine homolog of OTC cDNA and the ablation of E2a with a temperature-sensitive mutation. Infusion of this improved vector into the mouse model was associated with a complete normalization of liver OTC enzyme activity that persisted for at least 2 months with complete but transient correction in serum glutamine and urine orotic acid. These studies illustrate the utility of improved adenoviral vectors in the treatment of liver metabolic disease.
Ye
X
X
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Robinson
M B
MB
Batshaw
M L
ML
Furth
E E
EE
Smith
I
I
Wilson
J M
JM
D000256:Adenoviridae; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D003433:Crosses, Genetic; D003587:Cytomegalovirus; D005260:Female; D015316:Genetic Therapy; D005973:Glutamine / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology; D009954:Ornithine Carbamoyltransferase / Q000096:biosynthesis / Q000235:genetics; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D009963:Orotic Acid / Q000652:urine; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D013997:Time Factors; D014162:Transfection
D005973:Glutamine; D009963:Orotic Acid; D009954:Ornithine Carbamoyltransferase