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

• Published in: Gene therapy Vol. 20; no. 12; pp. 1188 - 1191
• Main Authors: Chandler, R J, Tarasenko, T N, Cusmano-Ozog, K, Sun, Q, Sutton, V R, Venditti, C P, McGuire, P J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2013; Nature Publishing Group
• Subjects: 631/61/201; 692/698/2741/288; 692/699/317; Adeno-associated virus; Adenoviruses; Ammonia; Ammonia - blood; Animal models; Animals; Argininosuccinate Synthase - deficiency; Argininosuccinate Synthase - genetics; Argininosuccinate Synthase - metabolism; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell Biology; Citrulline; Citrulline - blood; Citrullinemia - genetics; Citrullinemia - therapy; Dependovirus - classification; Dependovirus - genetics; Dependoviruses; Disease Models, Animal; Enzymatic activity; Gene Expression; Gene Therapy; Genetic aspects; Genetic Therapy; Genetic transformation; Genetic Vectors; Globulins; Hereditary diseases; Human Genetics; Humans; Hyperammonemia; Lethality; Liver; Liver - enzymology; Liver - virology; Metabolic diseases; Metabolic disorders; Mice; Nanotechnology; Organ Specificity; Phenotype; Phenotypes; Rodents; short-communication; Thyroxine; Thyroxine-Binding Globulin - genetics; citrullinemia; hyperammonemia; AAV8; urea cycle disorders
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2013.53

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.