Highly potent siRNA constructs and efficient delivery are an essential combination for harnessing the power of RNAi. It is the right therapy (UsiRNA or shRNA), delivered to the right place (specific tissue, cell and gene target) via the right approach (safe and effective delivery system) that provides for a potentially clinically successful RNAi-based therapeutic.
Development of an RNAi drug candidate in combination with a delivery system, to form the drug product, requires broad expertise and a deep understanding of the areas of biology (molecular and cellular), chemistry (dialkylated amino acid and peptide), microbiology (tkRNAi bacterial platform) and pharmaceutical sciences, and the interdependency of these areas for systemic, local, topical, or oral delivery of siRNAs to organs and individual cells for activity against specific gene targets.
Key considerations for the design of the RNAi drug candidate include:
- Protection of the siRNA from nuclease degradation prior to cell entry
- Intracellular stability of the siRNA
- Compatibility between the siRNA/shRNA and cellular RNAi machinery
- Elimination of off-target effects
- Avoidance of the immune surveillance mechanisms and cytokine induction
Key considerations for the delivery system include:
- Safe and effective systemic administration for transport via blood to the target site
- Safe and effective local or topical administration via direct application at the target site
- Safe and effective oral administration to target intestinal cells
- Optimization of formulation/delivery vehicle characteristics to achieve delivery to desired tissue
- Facilitation of cellular uptake at the target site and intracellular release of siRNA/shRNA
Marina is discovering and advancing to the clinic drug products comprised of siRNA constructs (UsiRNA) within novel DiLA2-based liposomes, which we have termed tauRNAi, or as an expressed RNA in a bacterial delivery system which we call tkRNAi. Matching the construct and delivery technologies to the disease ensures optimal delivery of highly potent siRNAs for activation of the RNAi process and down regulation of protein expression, the combined actions of which provide for efficacious RNAi-based therapeutics.