Delivering the right therapy to the right place, at the right time

The challenge of delivering effective RNAi-based therapeutics requires broad expertise and a deep understanding of biology (molecular and cellular); chemistry (lipid and peptide); routes of drug administration (systemic, local and topical); and the interdependency of these three areas for delivering siRNAs to organs, individual cells, and specific gene targets.

Challenges specific to designing siRNA structures include:

• Nuclease degradation prior to cell entry
• Cellular uptake of siRNA and intracellular degradation
• The specificity of siRNA interaction with cellular machinery
• Off-target effects
• Cytokine induction

Challenges specific to siRNA delivery include:

• Safe and effective systemic administration for transport via blood to target site
• Safe and effective local administration via direct application to target site
• Cellular uptake and intracellular distribution for effective gene silencing

To address these challenges, MDRNA is discovering and advancing to clinic drug candidates comprised of various siRNA constructs (Dicer substrates and meroduplexes) within novel liposome and peptide-based delivery systems to ensure optimal siRNA delivery, activation of the RNAi process, and down regulation of protein expression.

About Dicer substrates

Dicer substrates are oligonucleotides of approximately 25-27 nucleic acid base pairs which are processed intracellularly by the Dicer enzyme into shorter siRNA strands (RISC substrates - typically 19-23 base pairs) which then activate the RNAi pathway. Dicer substrates are believed to have unique RNAi characteristics including increased efficiency of RNAi activation since Dicer facilitates a “hand-off” of the substrate directly to the RISC protein complex. RISC substrates are not processed by Dicer and therefore would not see this advantage during RNAi activation. Of equal importance to its potential increased efficiency, is the prospect that Dicer substrates are amenable to direct conjugation of delivery moieties for targeting to specific cells and tissues.