Effective siRNA delivery to the right cells is a challenge given the complexity of the human body.
The use of our delivery systems is independent from the siRNA that is being administered and therefore each constitute a modular platform technology. We adopt a variety of approaches to address the delivery challenges:
GalNAc (N-Acetylgalactosamine) is a naturally occurring sugar that binds to the asialoglycoprotein receptor (ASGPR), which is highly expressed in the membrane of hepatocytes (liver cells). Coupling GalNAc sugars to stabilised siRNA molecules allows them to target liver cells and carry out their function, being shuttled into the cytoplasm as a result of the GalNAc-ASGPR binding.
GalNAc-siRNA conjugates can be administered subcutaneously, in a more patient-friendly way that removes the need for invasive intravenous infusions. This key advantage lowers the patient burden of GalNAc-siRNA drugs in comparison to more complex delivery systems such as liposomes, meaning that GalNAc-based therapies are an attractive solution for a wider selection of liver-centric disease areas. Given the size of this opportunity, developing GalNAc-siRNA drugs is the core focus of our Company.
Lipid nanoparticles, or liposomes, are essentially capsules made of a combination of lipids. Liposomes are able to mediate efficient siRNA delivery without requiring extensive chemical modification of the cargo siRNA and have shown promising results in the clinic, although they require invasive intravenous administration. We have developed liposomal systems able to deliver siRNA molecules to a variety of organs and cell types, including liver, lung and vascular endothelium.
As liposomes are large structures, their composition can be optimised to deliver larger cargos such as mRNA (to replace or up-regulate gene expression) and the tools needed to trigger gene editing through CRISPR/Cas9. We have demonstrated that our liposomes can mediate in vivo target mRNA delivery as well as gene disruption using an entirely RNA-based approach.
Our chemically modified siRNA molecules, designed to retain stability in the bloodstream without stimulating the immune system, are able to target certain kidney cells without the need for a delivery system when given intravenously. Naked siRNAs can also be administered intravitreally in order to target the eye. Both of these approaches are being used by our licensee Quark Pharmaceuticals in several of their clinical stage candidates (QPI-1002 and PF-655 based programmes).