What is RNA interference (RNAi)?

RNAi is a biological process that occurs naturally within our cells to help regulate gene expression. The mechanism by which RNAi mediates its biological function is specific targeting of messenger RNA (mRNA) molecules, which carry the instructions cells need to make proteins out of the genetic manual encoded in our DNA.

Our short interfering RNA (siRNA) therapeutics are synthetic molecules that harness this cellular process to silence the expression of disease-associated genes in a highly specific manner. An siRNA medicine designed to target a specific gene will, as part of an RNA-induced silencing complex (RISC), bind to its target mRNA and trigger its degradation. As a result, no disease-associated protein will be produced in the cell.

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Ability to safely silence any gene in the genome

RNAi medicines are next-generation therapeutics, and their design is markedly accelerated relative to traditional drug modalities because it is based on the human genetic code, which we now know. Other advantages of RNAi therapeutics include:

  • High specificity against their target gene, thus minimising potential off-target effects
  • No druggability issues, being able to silence virtually any gene in the genome
  • Long duration of action, supporting infrequent administration and reduced patient burden
  • Reversible effects (no changes to DNA)
  • Good safety profile
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Cell type-specific delivery to the liver

An additional level of specificity can be achieved by coupling siRNA molecules to delivery systems for cell type-specific targeting. Our siRNA constructs are conjugated to GalNAc (N-Acetylgalactosamine) moieties, which mediate highly specific delivery to hepatocytes in the liver. As the liver is a highly active organ, hepatocyte targeting unlocks opportunities in a wide variety of therapeutic areas.

This cell type specificity spares other cell types in the body and ensures that therapeutic levels of the therapeutic reach target cells. Our siRNA medicines also incorporate optimised chemistries to maximise their therapeutic activity and, together with GalNAc, enable subcutaneous administration.

Hepatocytes are highly metabolically active cells and their targeting enables the development of therapeutic strategies in a variety of therapeutic areas, including cardiovascular, metabolic, renal and rare diseases. Leveraging our computational platform, we have built the largest hepatocyte-specific knowledge graph as a differentiating in silico resource to interrogate liver biology.

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Our comprehensive hepatocyte biology map

Selecting the right target gene

While GalNAc-siRNA conjugates enable highly specific therapeutic interventions, it is crucial to understand the wider biological context involved in a particular disease setting. In complex diseases, only once the full complexity of relevant disease processes is understood can the best target genes be identified.

Our computational platform and hepatocyte knowledge graph are uniquely suited to drive the identification of better, novel siRNA targets. We routinely assess therapeutic hypothesis in silico and evaluate the downstream biological impact of silencing a particular target gene in a disease setting before investing resources in the discovery and development of our siRNA therapeutics. Our approach results in increased confidence in early therapeutic programmes ahead of entering the wet lab.

Our in silico network models allow us to assess the impact of potential therapeutic interventions in the human biology of interest, enabling us to rank target genes ahead of experimental validation.