In vivo RNA interference strategies against adenoviruses

Patients with an impaired immune system such as HIV-positive individuals or solid organ and particularly hematopoietic stem cell transplant recipients are at high risk of undergoing life- threatening infections with human adenoviruses. Among stem cell transplant recipients with systemic infections mortality rates almost as high as 80% have been reported. The efficacy of commonly used drugs to treat adenovirus infections is limited and frequently associated with toxicity. Alternative drugs are still under investigation. Hence, given the fact that numbers of solid organ and hematopoietic stem cell transplant recipients are constantly rising, alternative treatment options are highly needed. Short interfering RNAs (siRNAs) and artificial microRNAs (amiRNAs) are a class of artificial small RNAs that can bring about the inactivation of cellular and viral genes via the RNA interference (RNAi) pathway. In a previous project led by the investigators highly potent siRNAs and amiRNAs with activity against components of the adenoviral DNA replication machinery that can effectively inhibit the replication of human adenoviruses in cell culture experiments were developed and characterized. The project is aimed at investigating if adenovirus infections can be inhibited by these RNAi- triggering small RNAs in vivo, and which of the 2 approaches (i.e. siRNA versus amiRNA) is more effective. RNAi-based inhibition of adenoviruses is supposed to be assessed in the Syrian hamster model which is able to mimic adenovirus infections in humans. Moreover the project aims at investigating if concomitant introduction of a particular gene into adenovirus-infected cells can enhance the RNAi-based inhibition of adenovirus multiplication. One of the 2 small RNA-based approaches is anticipated to lead to the selective amplification of the RNAi-triggering RNAs in adenovirus-infected cells and transfer to neighbouring cells where they are supposed to inhibit the otherwise uncontrolled multiplication of spreading adenoviruses. In summary, the project is not only supposed to investigate novel approaches to potentially inhibit life-threatening adenoviruses in a future therapeutic scenario, but also to provide an example how antiviral effectors can specifically be multiplied when coming in contact with virus-infected cells. This strategy may be applicable to the therapy of other virus infections as well.