Sirnaomics Science Science

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.

Sirnaomics RNAi Drug: STP705

The video explains how the drug is made and delivered.

The figure (below) explains the mechanism of the drug action inside the cells.

Sirnaomics RNA

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)

Sirnaomics has developed a ‘4D’ suite of tools that allows:

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.

Sirnaomics uses a proprietary Polypeptide Nano-Particle (PNP) to protect and deliver our siRNA cargo to cells.

The PNP is composed of a branched Histidine Lysine polymer that has an extensive literature on its use across a number of oncology cell models. This Polypeptide nanoparticle provides a number of advantages for our therapeutic platform:
1
The peptide is composed of natural amino acids so that degradation produces natural, non-toxic, products.
2
The PNP consists of a branched Histidine Lysine Polypeptide (HKP) that is readily synthesized. This PNP wraps around the siRNAs and serves to protect them from the surrounding environment while in the bloodstream. Once in the target cell though, the Histidine groups protonate and allow release of the payload into the cytoplasm where the siRNAs can then induce gene silencing.
3
Each PNP can carry multiple siRNA sequences. Delivery of multiple siRNAs can produce a synergistic effect (e.g. by targeting more than one essential gene in cancer cells we see a synergistic effect on cell killing resulting in better efficacy). Our target gene discovery and siRNA validation programs seek to leverage this benefit by identifying these synergistic targets in cancer cells.
4
Consistent sized nanoparticles can be manufactured by mixing HKP with the siRNAs to be carried. The size of these particles is typically 100-150nm but recent work suggests that we can further tune the size by changing the rate of mixing between the 2 solutions. Very fast mixing can produce smaller particles.
5
Delivery of the PNPs can be via intradermal injection (e.g. for Non-Melanoma Skin Cancer (NMSC)) or by intravenous (IV) administration (e.g. for treating liver fibrosis or cancer). Our lead product (STP705) reduces expression of both TGF-β1 as well as Cox-2 – targets implicated in inflammation, fibrosis and oncology indications and therefore providing a foundational platform.
6
Injected IV in animals, the PNP is rapidly observed in the liver – specifically it is internalized in cells with importance for fibrosis treatment and oncology indications (e.g. Stellate cells, Hepatocytes and Longitudinal Sinusoidal Endothelial cells). We have also seen efficacy when delivered intratumorally and even see synergy with existing therapies (e.g. in Cholangiocarcinoma xenografts) when administered IV.
7
Publications, by Sirnaomics and others, have indicated that the PNP can home to tumors and deliver siRNAs to inhibit tumor growth via the Enhanced Permeability and Retention (EPR) effect.

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:

  • Improve efficacy compared with targeting one gene alone
  • Broaden the therapeutic effect to provide benefit to more patients.

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.