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      Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector

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          Abstract

          A novel selectively targeting gene delivery approach has been developed for advanced hepatocellular carcinoma (HCC), a leading cause of cancer mortality whose prognosis remains poor. We combine the strong liver tropism of serotype-8 capsid-pseudotyped adeno-associated viral vectors (AAV8) with a liver-specific promoter (HLP) and microRNA-122a (miR-122a)-mediated posttranscriptional regulation. Systemic administration of our AAV8 construct resulted in preferential transduction of the liver and encouragingly of HCC at heterotopic sites, a finding that could be exploited to target disseminated disease. Tumor selectivity was enhanced by inclusion of miR-122a-binding sequences (ssAAV8-HLP-TK-122aT4) in the expression cassette, resulting in abrogation of transgene expression in normal murine liver but not in HCC. Systemic administration of our tumor-selective vector encoding herpes simplex virus-thymidine kinase (TK) suicide gene resulted in a sevenfold reduction in HCC growth in a syngeneic murine model without toxicity. In summary, we have developed a systemically deliverable gene transfer approach that enables high-level expression of therapeutic genes in HCC but not normal tissues, thus improving the prospects of safe and effective treatment for advanced HCC.

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          Author and article information

          Journal
          Human Gene Therapy
          Human Gene Therapy
          Mary Ann Liebert Inc
          1043-0342
          1557-7422
          February 2015
          February 2015
          : 26
          : 2
          : 94-103
          Affiliations
          [1 ]Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, United Kingdom.
          [2 ]Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom.
          [3 ]Division of Medicine, UCL Centre for Advanced Biomedical Imaging, University College London, London WC1E 6DD, United Kingdom.
          [4 ]NHS Blood and Transplant, London W1W 8NB, United Kingdom.
          [5 ]Institute of Nuclear Medicine and Department of Chemistry, University College London, London WC1H 0AJ, United Kingdom.
          [6 ]Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 33105-3678.
          [7 ]Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London NW3 2QG, United Kingdom.
          Article
          10.1089/hum.2014.052
          4326028
          25569358
          © 2015
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