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

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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.