Long-term correction of ammonia metabolism and prolonged survival in ornithine transcarbamylase-deficient mice following liver-directed treatment with adeno-associated viral vectors

Mol Ther. 2006 Jul;14(1):25-33. doi: 10.1016/j.ymthe.2006.03.009. Epub 2006 May 3.


The purpose of this study was to determine the efficacy of novel recombinant adeno-associated viral (AAV) vector constructs in correcting metabolic defects in the liver in two strains of ornithine transcarbamylase (OTC)-deficient mice (spf and spf-ash). AAV vectors expressing mouse OTC were produced with capsids from AAV2 and the novel serotypes AAV7, 8, and 9. OTC-deficient mice were infused with these vectors as well as a control AAV2/8 vector expressing LacZ. In vivo activity of OTC was assessed by measuring a surrogate marker, urine orotate. The novel vectors restored orotate levels to virtually normal 15 days after infusion, and each persisted to 1 year posttreatment. Liver OTC enzyme activity in spf mice was substantially higher in animals receiving novel vectors compared to those receiving AAV2 vectors. Animals receiving novel OTC-expressing vectors lived longer than those treated with AAV2 OTC or untreated controls, and they were tolerant to a challenge with NH3 at 21 days and beyond, which caused severe morbidity in control OTC-deficient animals. Numerous mice, representative of all treatment groups followed for +250 days, were observed to have either nodules or discrete tumors in the liver, the etiology of which is the subject of a companion paper.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonia / metabolism*
  • Ammonia / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Dependovirus / genetics*
  • Female
  • Genetic Therapy / methods
  • Genetic Vectors / genetics
  • Liver / enzymology
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Ornithine Carbamoyltransferase / genetics*
  • Ornithine Carbamoyltransferase / metabolism
  • Ornithine Carbamoyltransferase Deficiency Disease / enzymology
  • Ornithine Carbamoyltransferase Deficiency Disease / genetics
  • Ornithine Carbamoyltransferase Deficiency Disease / therapy
  • Orotic Acid / urine
  • Survival Analysis
  • Time Factors


  • Orotic Acid
  • Ammonia
  • Ornithine Carbamoyltransferase