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首页> 外文期刊>Human gene therapy. Clinical development >Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector
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Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector

机译：使用重组腺相关病毒载体优先靶向弥漫性肝肿瘤

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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.
机译：已经开发出一种针对晚期肝细胞癌（HCC）的新型选择性靶向基因递送方法，HCC是癌症死亡的主要原因，其预后仍然很差。我们结合血清特异性8衣壳假型腺相关病毒载体（AAV8）与肝脏特异性启动子（HLP）和microRNA-122a（miR-122a）介导的转录后调节的强大肝脏嗜性。我们的AAV8构建体的系统性给药导致异位点肝脏的优先转导和令人鼓舞的HCC的发现，这一发现可用于靶向传播的疾病。通过在表达盒中包含miR-122a结合序列（ssAAV8-HLP-TK-122aT4）增强了肿瘤的选择性，导致正常鼠肝中的转基因表达被废除，而在HCC中则被废除。全身注射编码单纯疱疹病毒-胸苷激酶（TK）自杀基因的肿瘤选择性载体，在没有毒性的同基因鼠模型中导致HCC生长减少了七倍。总而言之，我们已经开发出一种系统可传递的基因转移方法，该方法可在HCC而非正常组织中高水平表达治疗基因，从而改善安全有效治疗晚期HCC的前景。

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