Functional Genomics Reveals Major Cause of Inflammatory Bowel Disease, Discovered by UK Scientists
Background
Scientists at the Francis Crick Institute have discovered a major driver of inflammatory bowel disease (IBD) that could be used as a drug target. The Francis Crick Institute team collaborated with scientists from Imperial College London and University College London and published their findings in Nature.
IBD refers to the group of autoimmune disorders that includes Crohn's disease and ulcerative colitis. About 5% of the world's population, one in ten brits suffer from autoimmune diseases like IBD, and this figure is on the rise.
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27 year old Lauren Golightly was diagnosed with Crohn's disease in 2018. She said: "One of the hardest things about having Inflammatory Bowel Disease ( IBD) is the uncertainty around it. I still experience flare-ups and can still spend quite a bit of time in hospital."
Although there are treatments available – notably dietary restrictions, steroids, and sometimes surgery – these therapies often only provide symptomatic relief and do not target the cause of the condition.
"Every year, more than 25,000 people are told that they have Inflammatory Bowel Disease," said Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn's & Colitis UK.
She continued: "Crohn's and Colitis are complex, lifelong conditions for which there is no cure, but research like this is helping us to answer some of the big questions about what causes them."
Tracking down the cause of IBD
James Lee, Group Leader of the Genetic Mechanisms of Disease Laboratory at Francis Crick, led the research, he explained: “Using genetics as a starting point, we’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases."
The cause lies in a section of non-coding DNA: an intergenic region on chromosome 21q22 (chr21q22). This region has been associated with a range of inflammatory diseases, and further reasoning suggested that the region on chr21q22 could be enhancing the gene ETS2 in macrophages.
Part of this reasoning stemmed from higher levels of this gene being correlated with higher risk of IBD: "increased ETS2 expression in monocytes and macrophages […] was found to have the same genetic basis as inflammatory disease risk." The Crick team investigated this connection by deleting the chr21q22 enhancer region using CRISPR-Cas9, and sure enough it significantly reduced the upregulation of ETS2.
Another step towards the cause of IBD was the discovery that ETS2 regulated the inflammatory function of macrophages. The team conducted a CRISPR-Cas9 loss-of-function analysis by disrupting ETS2 in macrophages, this led to a reduction in multiple inflammatory signals. They concluded that "ETS2 is essential for multiple inflammatory functions in human macrophages."
This groundwork allowed the team to identify ETS2 as a coordinator for macrophage inflammation and as having a key pathogenic role in IBD. Spatial transcriptomic and scRNA-seq data from patient samples further confirmed the connection. Samples taken from Crohn's disease patients expressed ETS2 more highly than healthy samples.
The potential for new drugs
Lee commented: "Excitingly, we’ve shown that this can be targeted therapeutically, and we’re now working on how to ensure this approach is safe and effective for treating people in the future."
Due to the fact that there aren't any ETS2 inhibitors available, the team instead set about blocking the gene indirectly. Using a database of cellular signatures, NIH LINCS, the scientists at Crick predicted that MEK inhibitors might be able to modulate this pathway.
Putting this theory to the test, the researchers then followed up with in vitro and ex vivo validation. They cultured intestinal biopsies from active and untreated IBD along with MEK inhibitors or a control and found that MEK inhibitors were able to significantly reduce inflammation in the samples.
The group now want to take these findings further by developing the delivery mechanism of MEK inhibitors so that they can directly target macrophages. To do this, they are partnering with London-based translational research company LifeArc.
The paper says that their methodology: "illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities."
Golightly said that "learning about this research is so exciting and encouraging. I am hopeful this could potentially make a difference for myself and so many other hundreds of thousands of people living with IBD.”
