title: Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1.
abstract: 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.
authors.affiliation: Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Chandler
authors.forename: T N
authors.initials: TN
authors.lastname: Tarasenko
authors.forename: K
authors.initials: K
authors.lastname: Cusmano-Ozog
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.forename: V R
authors.initials: VR
authors.lastname: Sutton
authors.forename: C P
authors.initials: CP
authors.lastname: Venditti
authors.forename: P J
authors.initials: PJ
authors.lastname: McGuire
mesh_terms: D000641:Ammonia / Q000097:blood; D000818:Animals; D001124:Argininosuccinate Synthase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002956:Citrulline / Q000097:blood; D020159:Citrullinemia / Q000235:genetics* / Q000628:therapy*; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000821:virology; D051379:Mice; D009928:Organ Specificity; D010641:Phenotype; D056825:Thyroxine-Binding Globulin / Q000235:genetics
chemical_list: D056825:Thyroxine-Binding Globulin; D002956:Citrulline; D000641:Ammonia; D001124:Argininosuccinate Synthase