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Publication Detail
Preferential targeting of disseminated liver tumors using a recombinant adeno-associated viral vector.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Della Peruta M, Badar A, Rosales C, Chokshi S, Kia A, Nathwani D, Galante E, Yan R, Arstad E, Davidoff AM, Williams R, Lythgoe MF, Nathwani AC
  • Publication date:
  • Pagination:
    94, 103
  • Journal:
    Hum Gene Ther
  • Volume:
  • Issue:
  • Status:
  • Country:
    United States
  • Language:
  • Keywords:
    Animals, Capsid, Carcinoma, Hepatocellular, Dependovirus, Disease Models, Animal, Gene Expression Regulation, Genetic Engineering, Genetic Therapy, Genetic Vectors, Humans, Liver, Liver Neoplasms, Male, Mice, Mice, Inbred BALB C, Mice, SCID, MicroRNAs, Promoter Regions, Genetic, Recombinant Proteins, Simplexvirus, Thymidine Kinase, Tissue Distribution, Transplantation, Heterotopic, Viral Proteins
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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