Philippe-Vollmer-Barosa,Fraunhofer ITEM, Hannover

Human Parainfluenza Virus is the second most abundant pathogen in viral respiratory infections in infants and also has major health implications on immunocompromised high-risk patients such as lung transplant or hematopoietic stem cell transplant recipients. To date, there is no approved specific antiviral clinically available for this infection.
Based on recent successes of RNA-therapeutics, we have developed an inhaled siRNA-based antiviral targeting Parainfluenza infection.

To implement a readily adjustable drug pipeline and foster pandemic preparedness, we set up the iGUARD (integrated Guided Ultrafast Antiviral RNAi Drug development) platform. This includes in silico target prediction and customized screening, infection experiments in vitro, ex vivo (using human Precision-cut lung slices), and in vivo. We further developed an LNP-based formulation for aerosol delivery and tested this in an explanted isolated rat lung model as well as in vivo.

Here, we show successful enrolment of the platform for the generation of an siRNA drug candidate against Parainfluenza. The candidate showed efficient reduction of the viral load in vitro and ex vivo with IC50 values in the nM range, depending on the test system. No toxicity was observed in the test systems applied. The LNP formulation was stable upon nebulization with a mesh nebulizer and successfully delivered fluorescently labelled siRNA into the airway epithelium. Furthermore, the LNP-formulated siRNA showed initial efficacy in vivo after inhalation, reducing the viral load in lung tissue after prophylactic application.

In conclusion, we have generated a safe and efficient RNAi-drug candidate that shows in vivo efficacy after inhalation. We will further refine the preclinical development of the compound and drug product to pave the way towards clinical translation.
Philippe Vollmer Barbosa1,2, Franziska Dahlmann1, Katherina Schwarz1, Axel Schambach2 and Armin Braun1,

1Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; 2Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany