The core of Sirnaomics’ technology is centered on the use of RNA interference (RNAi) and a unique polypeptide nanoparticle (PNP) for delivery.
RNA interference (RNAi) is a biological process in which small interfering RNAs (siRNAs) silence gene expression by degrading targeted mRNA molecules. Andrew Fire and Craig Mello shared the 2006 Nobel Prize in Physiology or Medicine for their discovery of RNAi in worms, published in 1998. Since the discovery, evidence has been growing that RNAi promises to become a novel therapeutic modality. Twenty years later, this promise has been fulfilled – the first RNAi drug Onpattro was approved by the FDA in 2018.
Sirnaomics develops novel drugs using chemically synthesized RNAi triggers (short interfering RNAs or siRNAs) delivered to the targeted cells within the body by proprietary peptide nanoparticle (PNP) formulations.
The video explains how the drug is made and delivered.
The figure (below) explains the mechanism of the drug action inside the cells.
Mechanism of mRNA degradation by siRNA inside the cell. SiRNA delivered by nanoparticles is taken into the cells by endocytosis. Once released by the nanoparticle into the cytosol, siRNA is incorporated into the RNA-induced silencing complex (RISC), a protein–RNA complex that separates the strands of the RNA duplex and discards the sense strand. The antisense RNA strand then guides the activated RISC to anneal and cleave the target mRNA with a complementary sequence. The endonuclease argonaute-2 plays a key role in unwinding the duplex and downregulation of the specific mRNA. Following mRNA cleavage, the activated RISC is capable of many rounds of mRNA cleavage. (ref. from Q. Leng, M.C. Woodle, P.Y. Lu, A.J. Mixson; Drugs of the Future 2009, 34)
Research based Discovery of therapeutic gene/protein targets contributing to the development of disease
In Vivo Delivery of these molecules to diseased cells for therapeutic benefit and
In Silico Design of silencing agents (siRNA/miRNA) that reduce expression of these critical genes
Rapid Clinical Development of these products for specific therapeutic indications.
In Oncology (as well as in Fibrosis) we have determined that silencing more than one target can have a profound improvement in the efficacy of an RNAi therapeutic. In each therapeutic indication we therefore focus on the identification of 2 gene targets for silencing that produce an additive or synergistic effect when both are silenced in the same cell. By impacting multiple pathways in diseased cells we can:
We have applied a similar combination therapeutic approach to identify genes that, when silenced, improve the activity of approved Standard of Care therapeutic agents such as small molecules (e.g. Gemcitabine) or antibodies (e.g. Checkpoint inhibitors used for immuno-oncology). This approach will ensure that we produce therapeutics that augment existing treatment options for patients with disease as well as providing therapeutics for diseases with unmet medical need.