BEYOND RNAi - Novation is not an RNAi Company

RNA interference (RNAi) using siRNA (small inhibitors of RNA) is not the same as modulation of mRNA by small molecular weight compounds.

siRNA is a gene silencing approach, using nucleotide copies of specific RNA sequences to bring about destruction (silencing) of RNA, whereas Novation modulates RNA using small molecules.

Both modulation of mRNA and RNA interference (RNAi) are utilizing a normal cellular process for control and silencing of RNA. In the cell, mRNA is destroyed when not required, through either the inbuilt Stability Control Elements (SCEs) within the mRNA molecule allowing attack by enzymes (Novationís approach), or, through the production of small copies of the RNA which bind to the mRNA forming a duplex, which stimulates its destruction (RNAi approach).

RNA is normally single stranded and unlike DNA, which is double stranded, cannot exist in a double stranded form. If a double stranded RNA (dsRNA) is produced, it is recognized by the cell and specific enzymes are produced which then immediately destroy it Ė the RNAi response. The cell can thus utilize the creation of a dsRNA as a means of removing unwanted RNA. It does this by producing a complementary strand of RNA, which binds to the target RNA to form a double strand, and allows the duplex to be destroyed. This natural control mechanism has been copied and exploited by scientists as a means of highly specific interference with a gene of interest and has been used, with good effect, in cell assays to identify gene function. This essentially investigative tool is now being developed as a potential therapeutic approach. Recent evidence though is beginning to suggest that RNAi may not be producing a therapeutic response in the manner first thought and may also not be as specific as expected, rather is may actually be creating a generalized inflammatory response in the cells into which it is introduced.

Novationís mRNA gene silencing approach, which recognizes and targets the inbuilt degradation/stability elements within mRNA, is different, more powerful, of greater utility than RNAi, and uses easily administered small molecules rather than RNAi nucleotides.

Unlike RNAi, modulation of mRNA can also be used to activate gene expression, and thus is truly modulation of gene function, and more than just gene silencing.

There are other important and significant differences between the two approaches that affect the practical therapeutic application of mRNA modulation versus RNA interference. Although short, the molecules used in RNAi are nucleotide sequences which are at least 20 times bigger than small medicinal chemistry compounds and have a number of challenges to overcome. siRNA has a molecular weight of around 20,000 Da with attendant difficulties in delivery and release into cells. Novationís mRNA approach, on the other hand, uses small molecule compounds, less than 500 Da (one sixtieth the size), which may be delivered orally and are able to enter and be active within the cell.

As biologicals, siRNAs are relatively unstable and cannot penetrate the cell membrane. Delivery of the siRNA to its target is a major hurdle that has still not been effectively overcome. Also, biologicals, unlike small molecule therapeutics, are complicated and expensive to manufacture, store, or be easily administered. Novationís approach thus distinguishes itself from RNAi by achieving the same gene silencing result by use of modulation of mRNA stability, but uses small molecular weight compounds that are orally available and easier and cheaper to manufacture. Furthermore, modulation of mRNA stability can be used to stimulate protein production if required, therefore going beyond the capabilities of RNAi.

MODULATION OF mRNA RNAi
Utilizes natural mechanism Utilizes natural mechanism
Gene silencing and gene stimulation Gene silencing only
Small molecules (<500 Da) Biologicals (20,000 Da)
Oral delivery Direct injection
Low cost of goods High cost of goods
Enter and are active in cells By themselves cannot enter cells