期刊
HUMAN GENE THERAPY
卷 26, 期 2, 页码 94-103出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2014.052
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资金
- Foundation for Liver Research, UK
- NIHR University College London Hospitals Biomedical Research Centre
- NIHR Programme Grant [RP-PG-0310-1001]
- King's College London
- UCL Comprehensive Cancer Imaging Centre CR-UK
- ASSISI Foundation of Memphis
- American Lebanese Syrian Associated Charities
- National Institutes of Health Research (NIHR) [RP-PG-0310-1001] Funding Source: National Institutes of Health Research (NIHR)
- Cancer Research UK [16463] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10071, RP-PG-0310-1001] Funding Source: researchfish
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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