Inhibition of SARS-CoV-2 with short interfering RNA (siRNA) in a lung-on-a-chip model

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The aim of this collaboration project between LMU and KUM is to optimize antiviral activity and delivery of short interfering RNA sequences (siRNAs) for coronavirus inhibition in an artificial lung model. The novelty of this approach consists in the optimization of the siRNA sequences and their delivery, in the assessment of strategies against viral escape, in the establishment of an infection model in a biomimetic lung model (lung-on-a-chip), and in the investigation of the aerosolizability of RNA nanoformulations for pulmonary dosing. The overarching goal of the project is to gain a better understanding of whether and how siRNA can be used to inhibit coronaviruses in the lungs for further development of inhalable RNA therapeutics. The innovative core of this project consists of the following elements: 1. The use of highly active siRNA sequences whose target regions are broadly conserved throughout different coronaviral species. 2. The optimization of siRNA sequences and their delivery for improved efficiency and reduced immunogenicity. 3. The identification of a potent strategy to prevent viral escape under therapy. 4. The investigation of necessary RNA doses and administration regimens for infection prevention as well as for inhibition of viral replication after infection. 5. The development of a virus infection model taking into account the lung environment on a microfluidic chip (lung-on-a-chip). 6. The investigation of the aersosolizability of the RNA nanoformulations for pulmonary dosing.