Della Peruta Marco, Badar Adam, Rosales Cecilia, Chokshi Shilpa, Kia Azadeh, Nathwani Devhrut, Galante Eva, Yan Ran, Arstad Erik, Davidoff Andrew M, Williams Roger, Lythgoe Mark F, Nathwani Amit C
1 Institute of Hepatology, Foundation for Liver Research , London WC1E 6HX, United Kingdom .
Hum Gene Ther. 2015 Feb;26(2):94-103. doi: 10.1089/hum.2014.052.
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.
针对晚期肝细胞癌（HCC），一种主要的癌症致死原因且预后仍然很差的疾病，已经开发出一种新型的选择性靶向基因递送方法。我们将血清型8衣壳假型腺相关病毒载体（AAV8）的强肝脏嗜性与肝脏特异性启动子（HLP）以及微小RNA-122a（miR-122a）介导的转录后调控相结合。全身给予我们构建的AAV8导致肝脏优先转导，并且令人鼓舞的是在异位位点的HCC也能转导，这一发现可用于靶向播散性疾病。通过在表达盒中包含miR-122a结合序列（ssAAV8-HLP-TK-122aT4）增强了肿瘤选择性，导致转基因在正常小鼠肝脏中不表达，但在HCC中表达。全身给予我们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，在同基因小鼠模型中导致HCC生长减少7倍且无毒性。总之，我们已经开发出一种可全身递送的基因转移方法，该方法能够在HCC而非正常组织中实现治疗性基因的高水平表达，从而改善晚期HCC安全有效治疗的前景。
