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)通常会引起人类的轻微疾病。然而，免疫抑制的患者往往会发生严重感染，并伴有严重肝炎，并可能导致死亡。由于现有的抗腺病毒治疗效果有限，迫切需要开发新的治疗方法。在我们之前的体外工作中，我们证明了当病毒感染在Ad复制周期的不同关键步骤同时被抑制时，抑制Ad感染是非常有效的。这涉及到抑制病毒的摄取、病毒蛋白的表达和病毒基因组的复制。该项目旨在表明，在活体中是否发生了同样的情况。对于这一提议，我们将比较单一疗法和联合疗法(A)合成的小干扰RNA抑制对腺病毒基因组复制至关重要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，其抑制Ad在肝细胞中的摄取，以及药物西多福韦，其抑制腺病毒基因组的复制。研究将在免疫抑制的叙利亚仓鼠中进行，在那里，人的Ad感染肝脏的肝细胞，受感染的动物发展为严重肝炎。