RNA interference (RNAi) is a naturally occurring process by which RNA molecules inhibit gene expression either pre- or post-transcriptionally. The discovery of RNAi led to a better understanding of gene regulation and opened the door to exciting new applications in research and therapeutics. The 2006 Nobel price was awarded in recognition of this revolutionary advance.
The RNAi pathway can be triggered by foreign DNA, double-stranded RNA, transposons, and pre-miRNAs. Frequently the RNA triggers are processed by enzymes (Drosha and Dicer) to yield short, double-stranded RNAs that are around 19 basepairs long. These are then loaded into RISC (RNA-induced silencing complex) and further processed such that only one strand of the RNA, the guide strand, remains. The guide strand directs this "mature RISC" to a complementary target sequence which is then either destroyed or otherwise regulated.
This naturally occurring process is now widely used to downregulate gene expression for research purposes and is being explored for promising new therapeutic approaches. Targets include mRNAs and viral RNAs that are not amenable to inhibition by traditional small molecule drugs and whose protein products have been previously classified as “not-druggable”.
Somagenics’ proprietary synthetic short hairpin RNA (sshRNAs) can be highly potent RNAi triggers, with IC50’s in the low picomolar range. They have some distinct advantages over the more familiar siRNAs: They are synthesized as a single chemical entity, simplifying their production and purification and eliminating the risk of excess guide or "passenger" strand remaining after annealing to form the active duplex. They have little or no off-target activities resulting from passenger-arm retention into the mature RISC, because the loop is sterically incompatible with the pocket of the Ago2 protein within the RISC that binds the free 5’-phosphate of the guide strand.
sshRNAs differ from longer shRNAs, such as are typically used in vectors expressing siRNA precursors, in that they are too short to be Dicer substrates. Because they are synthetic molecules instead of vector-expressed products, the dosage and half-life in the body can be precisely controlled, with little or no interference with endogenous miRNA processing.
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Advantages of sshRNA® RNAi Effectors
- Single chemical entity
- Simplified production, purification and formulation
- More potent (Siolas 2004, Ge 2010)
- Loop blocks off-target effects caused by retention of passenger strand in Ago2
- Small size of loop, blunt end blocks exonuclease degradation
over conventional expressed shRNA
- Precise and customizable chemical modification patterns
- Non-Dicer processing eliminates off-target effects caused by retention of passenger strand
- Dosage more controllable
sshRNA®s have no significant stimulatory effects in vivo
In vivo experiments confirm low immunostimulatory activity by chemically modified sshRNAs. CD1 ICR mice were administered 2.5 mg/kg LNP-formulated sshRNA (SG220) or LNP-formulated control siRNAs (LUC-U/U, LUC) by intravenous injection. After 4 hours, blood cytokine (left panel) and liver IFIT1 mRNA levels (right panel) were determined. The values shown are mean and standard deviation of measurements from each group of four mice. This experiment was conducted in collaboration with Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada.
Legal and Patent Information
These products are covered by one or more patents, trademarks and/or copyrights owned or controlled by SomaGenics, Inc. No right under any other patent claims to methods, apparatus or reagents is conveyed expressly, by implication, or by estoppel. This product is intended for Research Use Only and may not be transferred to third parties, resold, modified for resale or used to manufacture commercial products without prior written approval of SomaGenics, Inc. For more information about commercial rights, please contact SomaGenics.