RNA sequencing bridges preclinical models and clinical applications

'In recent years, we have developed and validated several immunological challenge models,' says Dr Matthijs Moerland, Research Director of Immunology. 'We are now at a point where we have a suite of options that we can offer to our customers. But, of course, we also continue to develop and refine our tools. That is why we are now conducting RNA sequencing to be able to map molecular responses to a challenge in even more detail'.

The Immunology group’s challenge models trigger a specific immunological response to show the effect of a candidate drug in a healthy study participant. Often, researchers combine a skin response with ex vivo challenges in immune cells from a participant's blood. In addition to skin tests, CHDR offers the option of a systemic LPS (bacterial lipopolysaccharide) challenge. LPS activates innate immunity in the skin or systemically via TLR4 (Toll-like receptor 4). To activate TLR7, imiquimod is applied to the skin. Cellular immunity is studied using vaccinations with a protein that humans normally never come into contact with, keyhole limpet hemocyanin (KLH). In recent years, Moerland and his colleagues have increasingly used these various immune challenge models in the evaluation of novel investigational drugs.

'We are now going to look in much greater detail at the molecules involved in the imiquimod challenge using RNA sequencing,' says Moerland. 'We noticed that there are clinical and immunological differences between our imiquimod model in humans and the preclinical imiquimod model in mice. Our collaborators at Erasmus University Rotterdam have a lot of experience with the mouse model. The RNA sequencing data will help us to explain the similarities and differences between TLR7 responses in mice and in humans and extend the potential application of the imiquimod model in clinical research.'

In the approach taken so far by Moerland and his colleagues in collaboration with the Dermatology group, imiquimod-treated skin was examined with the various imaging techniques of CHDR’s DermaToolbox. In biopsies the researchers looked for specific immune cells and cytokines. 'We look at a limited number of predetermined endpoints based on preclinical models and previous clinical experience,' says Moerland. 'With RNA sequencing data, from the very moment imiquimod hits TLR7, we can see which pathways are turned on and how long they stay on and what happens downstream. We expect that this will soon enable us to better choose endpoints that are relevant for specific drugs or disease states. This ties in nicely with the efforts of Robert Rissmann and the Dutch dermatological consortium, which aims to characterise detailed molecular profiles for various immunodermatological disorders. We can then go two ways: looking back at the preclinical model and looking ahead to possible clinical applications of a compound. The immune challenge model is the link bridging both. Our aim is to answer the question: what do the results of our study in healthy participants tell us about the indications in which this drug could be effective?'