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

Gene Therapy volume 20, pages 1188–1191 (2013)Cite this article

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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.

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Acknowledgements

For this work, RJC, TNT, CPV, and PJM were supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Thanks to the National Human Genome Research Institute mouse core for mouse care and technical assistance.

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Author notes

  1. R J Chandler and T N Tarasenko: These authors contributed equally to this work.

Authors and Affiliations

  1. Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    R J Chandler & C P Venditti

  2. Physician Scientist Development Program, Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    T N Tarasenko & P J McGuire

  3. Department of Genetics and Metabolism, Children’s National Medical Center, Washington, DC, USA

    K Cusmano-Ozog

  4. Biochemical Genetics Laboratory, Baylor College of Medicine, Houston, TX, USA

    Q Sun & V R Sutton

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  1. R J Chandler
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  2. T N Tarasenko
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  5. V R Sutton
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  7. P J McGuire
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Correspondence to P J McGuire.

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Chandler, R., Tarasenko, T., Cusmano-Ozog, K. et al. Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1. Gene Ther 20, 1188–1191 (2013). https://doi.org/10.1038/gt.2013.53

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