About RNAi
RNAi is considered to be one of the most important discoveries in the field of biology in the last decade. The scientists who discovered the mechanism were awarded the 2006 Nobel Prize in Medicine for their discovery. RNAi is a naturally occurring process that takes place inside cells, and includes processes whereby RNA molecules can profoundly suppress the production of specific proteins. Intense research activity has now uncovered a complex molecular mechanism responsible for RNAi that is transforming the method by which drug targets are discovered and validated. Furthermore, synthetic RNA molecules, including small interfering RNA (siRNA) and multivalent RNA (MV-RNA), among others, are being developed as drug candidates to specifically suppress the production of disease-related proteins through RNAi.
Small interfering RNA (siRNA) are synthetic RNA molecules designed to suppress the production of proteins through the mechanism of RNA interference (RNAi). Sequencing of the human genome has provided the information needed to design siRNA therapeutics directed against a wide range of disease-causing proteins. Based on the mRNA sequence for the target protein, a siRNA therapeutic can be designed relatively quickly compared to the time needed to synthesize and screen conventional small molecule drugs. Further, siRNA-based therapeutics are able to bind to a target protein mRNA with great specificity. When siRNA are introduced into the cell cytoplasm they are rapidly incorporated into an RNA-induced silencing complex (RISC) and guided to the target protein mRNA, which is then cut and destroyed, preventing the subsequent production of the target protein. The RISC can remain stable inside the cell for weeks, destroying many more copies of the target mRNA and maintaining target protein suppression for long periods of time.
Multivalent RNA (MV-RNA) provides 3-in-1 RNA capabilities for multisite RNA interference. A single MV-RNA molecule can supress one gene at several sites,
Tekmira's Expertise Combined with MV-RNA
Development of RNAi therapeutic products is currently limited by the instability of the RNA molecules in the bloodstream and the inability of these molecules to access target cells or organs, following intravenous, or systemic, administration, and their inability to gain entry into the cell cytoplasm, where they carry out their action. Delivery technology is necessary to protect these drugs in the blood stream following administration, allow efficient delivery to the target cells and facilitate cellular uptake and release into the cytoplasm of the cell. Tekmira's LNP technology has been shown in preclinical studies to enable RNAi therapeutic products by overcoming these limitations, allowing efficient and selective ‘silencing’ or reduction of certain target proteins. We believe that we are strongly positioned to take advantage of the need for delivery technology that can efficiently encapsulate RNA molecules and deliver them to sites of disease. We and our partners are advancing RNAi therapeutic product candidates using our LNP technology as the delivery vehicle to access target tissues and cells.
RNAi has the potential to generate a broad new class of therapeutic drugs that take advantage of certain of the body’s own natural processes to silence genes—or more specifically to eliminate specific gene-products, or proteins, from the cell. While there are no RNAi therapeutic products currently approved for commercial use, there are a number of RNAi therapeutic products in development and several in human clinical trials. RNAi therapeutic products have wide potential applicability as they can silence, or eliminate the production of disease causing proteins from cells, thus creating opportunities for therapeutic intervention that have not been achievable with conventional drugs.
About siRNA
About Multivalent RNA
or suppress multiple genes all at once. This new design enables greater potency and can minimize off target effects of RNAi drugs.
The Molecule
MV-RNA is comprised of three RNA guide strands that can each be incorporated into the RNA induced silencing complex (RISC). Each RNA strand is parially complimentary to the next, and form the three RNA-like arms of a MV-RNA molecule. Each arm of MV-RNA contain a specific 3’ signal to initiate loading into RISC.
The Mechanism
MV-RNA function similiarily to other RNAi molecules by guiding RNAi activity via RISC, but MV-RNA triple the RISC loading. Each MV-RNA arm is able to load into RISC and guide the silencing of the target mRNA. As shown in the two graphics below, the three guide strands of MV-RNA can be designed against multiple sites on a single gene OR single sites on multiple genes -- a novel function of MV-RNA.
MV-RNA: Multi-site RNAi
MV-RNA: Multi-gene RNAi
MV-RNA technology is synergistic with Tekmira’s existing technology platform and expertise including our LNP delivery technology as well as our broad understanding of RNA payload design. Leveraging our know-how and applying it to the MV-RNA technology allows for accelerated development of new RNAi therapeutics based on MV-RNA technology.
The Importance of Delivery