Refinement and assessment of a novel adenovirus targeting platform for application to human gene therapy

基因治疗正在迅速发展成为治疗或阻止许多人类疾病进展的有效方法。第一批基因治疗产品最近在中国获得许可（用于癌症治疗）。因此，利用基因治疗人类疾病是提供有效和持久疗法的现实机会，特别是那些缺乏最佳药物治疗的疾病。基因治疗的一个绝对关键的方面是基因递送，即用于将治疗货物递送到体内正确的细胞和组织的方法。基因递送通过具有将治疗性DNA转移到细胞中的能力的“载体”来实现-这些载体可以是非病毒的或基于病毒的。腺病毒载体通常用作基于病毒的递送系统，并且目前在基因治疗的所有正在进行的临床试验中约25%使用。这些病毒的优点是它们能够将基因转移到广泛的细胞中，因此这使它们适合于广泛的基因治疗应用。我们小组的研究最近通过发现腺病毒使用在宿主血液中循环的蛋白质感染宿主内的细胞而产生了影响。也就是说，当病毒被注射到血液中时，病毒与血液中一种称为凝血因子X的蛋白质相互作用。这种相互作用非常迅速和强烈，并允许病毒与肝脏中表达的受体结合。这就是为什么病毒具有如此强大的将基因转移到肝细胞中的能力。这并不总是有用的，因为我们希望将病毒靶向肝细胞以外的细胞（如癌细胞、肺细胞和肾细胞）。我们现在（通过2010年底结束的BBSRC的资助）开发了一种腺病毒，它完全去除了与凝血因子X结合的能力。这消除了基因转移到肝脏后，注射到血液中的修改病毒。我们现在希望申请资金来进一步发展这项工作，并询问病毒现在是否可以有效地靶向那些对潜在新疗法感兴趣的细胞类型。我们将利用这笔赠款来完善病毒，包括每种细胞类型的“靶向系统”，并使用合适的细胞和模型测试每个系统的靶向能力。我们期望我们的工作将对基因治疗社区具有广泛的吸引力，并对这种病毒的开发和改进产生影响，以用于未来的临床应用。

Gene therapy is rapidly developing into an effective method to cure or halt the progression of many human diseases. The first gene therapy products have been licensed recently in China (for cancer therapy). Therefore, the use of genes to treat human disease is a realistic opportunity to provide efficient and lasting therapies, especially those diseases that lack optimal drug-based therapies. An absolutely critical aspect of gene therapy is gene delivery, i.e. the method that is used to deliver the therapeutic cargo to the correct cells and tissues in the body. Gene delivery is achieved by a 'vector' that has the capability of transferring the therapeutic DNA into cells - these vectors can either be non-viral or viral-based. Adenovirus vectors are commonly used as a viral-based delivery system and are currently utilised in some 25% of all ongoing clinical trials in gene therapy. The advantages of these viruses is that they have the ability to transfer genes to a broad range of cells, hence this makes them suitable for a wide range of applications to gene therapy. The research from our group has made an impact recently through the discovery that the adenovirus uses a protein that circulates in the blood of the host to infect cells within the host. That is, when the virus is injected into the bloodstream, the virus interacts with a protein in the blood called coagulation factor X. This interaction is very rapid and strong and allows the virus to bind to receptors expressed in the liver. This is the reason why the virus has such a strong ability to transfer genes into liver cells. This is not always useful since we would like to target the virus to cells other than liver cells (such as cancer cells, cells in the lung and cells in the kidney). We have now (through funding from the BBSRC that ends in late 2010) developed an adenovirus that has its ability to bind to coagulation factor X completely removed. This eliminates gene transfer to the liver upon injection of the modified virus into the bloodstream. We now wish to apply for funding to further develop this work and ask whether the virus can now be efficiently targeted to those cells types that are of interest for potential new therapies. We will utilise this grant to refine the virus and include 'targeting systems' for each cell type and test the ability of each system to target using suitable cells and models. We expect that our work will have broad appeal to the gene therapy communuity and have an impact on development and refinement of this virus for future clinical applications.