Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1

Gene Ther. 2013 Dec;20(12):1188-91. doi: 10.1038/gt.2013.53. Epub 2013 Oct 17.


Citrullinemia type 1 (CTLN1) is an autosomal recessive disorder of metabolism caused by a deficiency of argininosuccinate synthetase. Despite optimal management, CTLN1 patients still suffer from lethal metabolic instability and experience life-threatening episodes of acute hyperammonemia. A murine model of CTLN1 (fold/fold) that displays lethality within the first 21 days of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy. An AAV serotype 8 (AAV8) vector was engineered to express the human ASS1 cDNA under the control of a liver-specific promoter (thyroxine-binding globulin, TBG), AAV8-TBG-hASS1, and delivered to 7-10 days old mice via intraperitoneal injection. Greater than 95% of the mice were rescued from lethality and survival was extended beyond 100 days after receiving a single dose of vector. AAV8-TBG-hASS1 treatment resulted in liver-specific expression of hASS1, increased ASS1 enzyme activity, reduction in plasma ammonia and citrulline concentrations and significant phenotypic improvement of the fold/fold growth and skin phenotypes. These experiments highlight a gene transfer approach using AAV8 vector for liver-targeted gene therapy that could serve as a treatment for CTLN1.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Ammonia / blood
  • Animals
  • Argininosuccinate Synthase / deficiency
  • Argininosuccinate Synthase / genetics*
  • Argininosuccinate Synthase / metabolism
  • Citrulline / blood
  • Citrullinemia / genetics*
  • Citrullinemia / therapy*
  • Dependovirus / classification
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Liver / enzymology*
  • Liver / virology
  • Mice
  • Organ Specificity
  • Phenotype
  • Thyroxine-Binding Globulin / genetics


  • Thyroxine-Binding Globulin
  • Citrulline
  • Ammonia
  • Argininosuccinate Synthase