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 UsiRNA

UsiRNAs are duplex siRNAs that are modified with non-nucleotide acyclic monomers termed unlocked nucleobase analogs (UNA), in which the bond between two adjacent carbon atoms of ribose is removed (see figure below). UsiRNAs are fully recognized by the RNAi machinery and provide for potent RNAi activity. Placement of UNA within UsiRNA minimizes the potential for off-target effects by the guide strand as well as undesired activity of the passenger strand. Furthermore, the change in sugar structure renders this nucleic acid analog conformationally flexible. The flexibility of the monomer escapes the surveillance mechanisms associated with cytokine induction, as well as provides protection from nuclease degradation.

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. While either strand of the siRNA duplex can assemble into the active RISC complex, only one strand (guide strand) of the siRNA duplex is incorporated into the RISC while the other strand (passenger 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 passenger 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 eliminate the off-target potential of the passenger strand by preventing its loading into RISC.

About the DiLA² Platform

The DiLA² Platform is a proprietary platform for creating novel liposomes from dialkyl-amino acids for delivery of siRNA. The platform 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 target tissue of interest. In addition, the platform is designed to permit attachment of various peptides to improve a variety of delivery characteristics including nanoparticle formulation, cellular uptake, endosomal release and cell/tissue targeting.