Adenovirus and coagulation factor interactions and the impact on virus stability and utility for gene therapy

腺病毒和凝血因子的相互作用以及对病毒稳定性和基因治疗效用的影响

• 批准号: BB/L027933/1
• 负责人: Andrew Baker
• 金额: $ 59.68万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL027933%2F1
• 关键词: Adenovirus; coagulation; factor; interactions; impact

Adenoviruses are a family of related viruses which cause mild infections in people and which have been converted into gene transfer vectors by blocking their ability to replicate in cells. This is achieved by crippling the ability of the virus to cause infection by deleting some if its DNA. The most common member of the adenovirus family used is adenovirus serotype 5 (Ad5). This allows the adenoviral vector to be used for gene therapy (the use of genes to treat human disease). In fact, adenoviruses are one of the most common vectors in use in gene therapy clinical trials because they are easy to work with, safe and are efficient at delivering genes to cells and tissues in the body. Depsite their common use we are still discovering new properties relating to this virus which highlights how important it is to understand it better in order that gene therapies can be made safer and more efficient (i.e. to optimise their use to treat patients). We made a recent discovery that when injected into the bloodstream adenovirus serotype 5 becomes coated in one of our own proteins in the blood called a coagulation factor. Interestingly, the coated virus then only delivers genes to the liver via the interaction with the coagulation factor and not a direct interaction between the liver and the viru (i.e. the coagulation factor acts as a bridge between the cell and the virus). The coagulation factor "sticks" to a specific protein on the coat of the virus called the hexon. Some other members of the adenovirus family also do this while others do not and the reason why this interaction has arisen is not well understood. Other groups have also suggested that either the host coats the virus with FX in order to help the immune system recognise it and remove it, while others have suggested that the virus itself "picks up" the coagulation factor to protect itself from the immune system. In this project we are going to investigate this important pathway further. We want to know whether the interaction is protective or not for the virus and if it is, whether the protection can be conferred to other viruses which do not bind to the coagulation factor. This will lead us to an understanding of how the virus and coagulation factor interact with different parts of our immune system. We also want to know exactly how the coagulation factor delivers the virus to the liver and whether modifying this pathway can lead to the development of gene therapies which are more efficient at delivering to other tissues in the body other than the liver, and this will broaden the use of the virus for treating patients through gene therapy. We will investigate these areas of adenovirus research by making changes to different parts of the virus's coat in order to allow or block the interactions and we will use genetic engineering approaches to achieve these important modifications. These experiments will help our further understanding of adenoviruses and ultimately lead to more optimal and safe vectors for all adenoviral gene therapy approaches.

腺病毒是一类相关病毒，可引起人类轻度感染，并通过阻止其在细胞中复制的能力而转化为基因转移载体。这是通过删除病毒的一些 DNA 来削弱病毒引起感染的能力来实现的。最常用的腺病毒家族成员是腺病毒血清型 5 (Ad5)。这使得腺病毒载体可用于基因治疗（利用基因治疗人类疾病）。事实上，腺病毒是基因治疗临床试验中最常用的载体之一，因为它们易于使用、安全且能够有效地将基因传递到体内的细胞和组织。尽管它们被广泛使用，但我们仍在发现与这种病毒相关的新特性，这凸显了更好地了解它以使基因疗法更安全、更有效（即优化其治疗患者的用途）的重要性。我们最近发现，当注射到血液中时，血清型 5 腺病毒会被血液中一种称为凝血因子的蛋白质包裹。有趣的是，包被的病毒仅通过与凝血因子的相互作用将基因传递到肝脏，而不是肝脏和病毒之间的直接相互作用（即凝血因子充当细胞和病毒之间的桥梁）。凝血因子“粘附”在病毒外壳上称为六邻体的特定蛋白质上。腺病毒家族的一些其他成员也会这样做，而其他成员则不会，并且这种相互作用发生的原因尚不清楚。其他团体也提出，要么宿主用 FX 包裹病毒，以帮助免疫系统识别病毒并将其清除，而另一些团体则认为病毒本身“拾取”凝血因子以保护自身免受免疫系统的侵害。在这个项目中，我们将进一步研究这一重要途径。我们想知道这种相互作用是否对病毒具有保护作用，如果是，是否可以将这种保护作用赋予其他不与凝血因子结合的病毒。这将使我们了解病毒和凝血因子如何与我们免疫系统的不同部分相互作用。我们还想确切地知道凝血因子如何将病毒传递到肝脏，以及修改这一途径是否可以导致基因疗法的发展，这些疗法可以更有效地将病毒传递到肝脏以外的身体其他组织，这将扩大病毒通过基因疗法治疗患者的用途。我们将通过改变病毒外壳的不同部分以允许或阻止相互作用来研究腺病毒研究的这些领域，并且我们将使用基因工程方法来实现这些重要的修饰。这些实验将有助于我们进一步了解腺病毒，并最终为所有腺病毒基因治疗方法带来更优化和更安全的载体。

项目成果

Defining a Novel Role for the Coxsackievirus and Adenovirus Receptor in Human Adenovirus Serotype 5 Transduction In Vitro in the Presence of Mouse Serum.

• DOI: 10.1128/jvi.02487-16
• 发表时间: 2017-06-15
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Lopez-Gordo E;Doszpoly A;Duffy MR;Coughlan L;Bradshaw AC;White KM;Denby L;Nicklin SA;Baker AH
• 通讯作者: Baker AH

The relevance of coagulation factor X protection of adenoviruses in human sera.

凝血因子X保护腺病毒在人血清中的相关性。

• DOI: 10.1038/gt.2016.32
• 发表时间: 2016-07
• 期刊: Gene therapy
• 影响因子: 5.1
• 作者: Duffy MR;Doszpoly A;Turner G;Nicklin SA;Baker AH
• 通讯作者: Baker AH