The project will develop novel and tunable RNA-based therapeutic modalities that target retinoic acid-inducible gene I (RIG-I) in order to activate the innate immune system and stimulate the production of interferons (IFNs). The project will achieve this objective through several steps, including refining the lead molecule dsRNA-1, which selectively activates RIG-I. The project will also leverage this platform to discover additional tunable agonists and antagonists to this key immune system modulator.  

Existing IFN treatments are predominantly protein-based, which necessitates the systemic administration of recombinant IFNs. This approach has several drawbacks, such as an increased potential for side effects and a lack of modulation. On the other hand, the new approach the project team is exploring selectively activates RIG-I, inducing type I/III IFNs. As a result, superior efficacy and safety profiles have been demonstrated when these molecules were administered intravenously, compared to IFN biologics or agents that stimulate the IFN pathway. In addition, the development of RNA therapeutics needs to overcome challenges that are inherent to RNAs, such as rapid degradation, non-specific immunogenicity, and delivery across various cell membranes. The project includes de-risking strategies for these challenges.