The RNAi process is initiated when a cell encounters dsRNA from an agent that enters the cellular cytoplasm such as viral RNA, a transposon, or microRNA. When this occurs, the RNase III-like protein Dicer is guided to the agent. Dicer cleaves the long dsRNA molecules into siRNA fragments 20-25 base pairs in length. The siRNA is then incorporated into the RNA-induced silencing complex (RISC) where the duplex is unwound into two strands. One of these strands (the guide strand) pairs with a complementary mRNA sequence, resulting in site-specific cleavage and silencing of the mRNA message. As the mRNA is degraded, the siRNA-RISC complex is released to pair with another mRNA target. Degradation of the mRNA reduces expression levels of the corresponding protein, effectively down-regulating (silencing) the gene without altering the DNA. It is this down-regulating action of RNAi that make siRNAs attractive as both a research tool and a potential therapeutic mechanism for treating diseases characterized by abnormal protein production.

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.

About meroduplex RNA

One of the intermediate steps in RNA interference involves the loading of small, double-stranded RNA duplexes (siRNAs) into the RNA Induced Silencing Complex, or RISC. Either strand of the siRNA duplex can assemble into the active RISC complex, and only one strand of the siRNA duplex is incorporated into the RISC while the other strand is degraded and removed. It has been generally accepted that a continuous siRNA duplex is required for efficient RISC assembly. However, MDRNA has shown that siRNAs containing a nick or gap in the sense strand can also be extremely active in RNAi. MDRNA has called these constructs "meroduplexes" to highlight the segmented nature of the siRNA duplex. The use of these types of siRNA constructs should help eliminate the off-target potential of the sense strand by preventing its loading into RISC.

About the DiLA² Platform

The DiLA² Platform is a proprietary platform for creating novel lipids from amino acids. The platform enables allows for modifying key aspects of the delivery system such as charge, linker and acyl chains such that the properties of the liposome are optimized for delivery to the target tissue of interest. In addition, the platform is amenable to attachment of targeting moieties for improved delivery specificity.