Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector
Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector
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DOI：
10.1089/hum.2014.052
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发表时间：
2015-02-01
影响因子：
4.2
通讯作者：
Nathwani, Amit C.
中科院分区：
文献类型：
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作者：
Della Peruta, Marco;Badar, Adam;Nathwani, Amit C.
一种新的选择性靶向基因传递方法已经被开发出来用于晚期肝细胞癌(HCC)，这是导致癌症死亡的主要原因，但预后仍然很差。我们将8型血清衣壳伪型腺相关病毒载体(AAV8)的强烈趋肝性与肝脏特异性启动子(HLP)和microRNA-122a(miR-122a)介导的转录后调控结合起来。我们的AAV8构建体的系统给药导致了肝脏的优先转导，令人鼓舞的是异位部位的肝细胞癌，这一发现可以被利用来针对播散性疾病。通过在表达框中加入miR-122a结合序列(ssAAV8-HLP-TK-122aT4)，提高了肿瘤的选择性，导致转基因在正常小鼠肝脏中的表达减少，但在肝癌中没有表达。我们的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系统给药后，在无毒性的同基因小鼠模型中，肝癌生长减少了七倍。综上所述，我们开发了一种系统可交付的基因转移方法，使治疗性基因在肝癌组织中高水平表达，而不是在正常组织中表达，从而改善了晚期肝癌安全有效治疗的前景。
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.