RNA interference based therapies for treatment of adenovirus infections in immunosuppressed host

基于 RNA 干扰的疗法用于治疗免疫抑制宿主的腺病毒感染

• 批准号: 211658021
• 负责人: Dr. Henry Fechner
• 金额: --
• 依托单位: Fachgebiet Angewandte Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/211658021?language=en
• 关键词: RNA; interference; based; therapies; treatment

Adenoviruses (Ad) typically induce mild diseases in humans. However, immunosuppressed patients often develop severe infections which are accompanied by severe hepatitis and can lead to death. As available anti-adenoviral therapies have limited efficiency the development of new therapies is urgently needed. In our previous in vitro work, we showed that the inhibition of Ad infection is very efficient when the virus infection is simultaneously inhibited at different critical steps of the Ad replication cycle. This regards the inhibition of the virus uptake, the expression of viral proteins and the virus genome replication. The project aims to show, whether the same occurs in vivo. For this propose we will compare as mono and combination therapy (A) synthetic small interfering RNAs inhibiting the expression of an adenoviral protein which is essential for adenoviral genome replication, (B) the drug warfarin and a genetically engineered coagulation factor X, which inhibit the Ad uptake into hepatocytes as well as the drug Cidofovir, which inhibit the replication of the adenoviral genome. Investigations will be carried out in immunosuppressed Syrian hamsters, where human Ad infects the hepatocytes of the liver and infected animals develop severe hepatitis.

腺病毒（Ad）通常在人类中引起轻微疾病。然而，免疫抑制的患者往往发展为严重感染，并伴有严重肝炎，并可导致死亡。由于现有的抗腺病毒治疗方法效率有限，迫切需要开发新的治疗方法。在我们之前的体外研究中，我们发现在Ad复制周期的不同关键步骤同时抑制病毒感染时，对Ad感染的抑制是非常有效的。这涉及到对病毒摄取、病毒蛋白表达和病毒基因组复制的抑制。该项目旨在证明，同样的情况是否发生在体内。对于这一建议，我们将比较单一和联合治疗(A)合成小干扰rna，抑制腺病毒基因组复制所必需的腺病毒蛋白的表达，(B)药物华法林和基因工程凝血因子X，它们抑制Ad进入肝细胞，以及药物西多福韦，它们抑制腺病毒基因组的复制。将在免疫抑制的叙利亚仓鼠中进行调查，其中人类Ad感染肝脏的肝细胞，受感染的动物发展为严重肝炎。