A new treatment paradigm for inflammatory conditions?
In the quest to develop effective drugs for inflammatory diseases, researchers are exploring new frontiers. A recent paper by Stankey et al (1) has shed light on promising directions, including:
• Targeting non-coding parts of the genome
• Multi-cytokine blocking
• Repurposing drugs for immunology
Here we look at each of these key points from the research and consider their implications for drug developers.
Non-Coding Genome: A New Frontier for Drug Targets
The human genome is vast, but only a small fraction of it codes for proteins. The rest, often referred to as the ‘dark matter’ of the genome, is non-coding. However, these non-coding regions are far from being ‘junk DNA’. They contain elements like promoters, silencers, and enhancers that regulate gene expression.
Recent advances in genomics have revealed that many disease-associated genetic variants reside in these non-coding regions. For instance, mutations within these essential DNA elements can potentially have as profound a biological impact as changes to a protein-coding sequence. This opens up a new avenue for drug targets. By targeting these non-coding elements, we could potentially modulate the expression of genes involved in inflammatory diseases.
However, investigating these non-coding areas of the genome has been extremely challenging. Causal genes may lie thousands of base pairs away from the coding gene, and their expression may depend on the cell type and external stimuli. This is why the latest research from Stankey et al published earlier this month, is so interesting.
New results for IBD
The research pivots on a gene desert in the chromosome 21q22 region, a stretch devoid of traditional coding genes but rich in genomic elements that control the behavior of distant genes. These non-coding regions, have been linked to various inflammatory diseases such as inflammatory bowel disease, ankylosing spondylitis, and others.
Key findings from the study underscore the ETS2 gene as a central regulator within this region, influencing macrophage behavior—a type of immune cell central to inflammatory responses. The overexpression of ETS2 in macrophages recreates the inflammatory characteristics of these diseases, making it a prime target for therapeutic intervention.
Multi-Cytokine Blocking: A Promising Approach
Traditional approaches to treating severe inflammatory diseases have concentrated on blocking the action of individual cytokines such as tumor necrosis factor and various interleukins.
However, the results of the recent study point to a more effective way of treating inflammatory diseases. By targeting upstream regulatory mechanisms like ETS2, it is possible to affect the production of multiple cytokines simultaneously—potentially a more efficient strategy than targeting individual cytokines. This could lead to therapies that are more broadly effective across various inflammatory conditions.
Repurposing Drugs for Immunology
One of the most intriguing aspects of the study is that the authors considered whether the disease pathway arising from ETS2 could be treated pharmacologically. As of today, ETS2 inhibitors don’t exist, however certain drugs can modulate the ETS2 pathway. This led them to consider MEK inhibitors, traditionally used in oncology settings, which are known to downregulate ETS2 genes. Treating macrophages with a specific MEK inhibitor, they observed potent anti-inflammatory activity with levels similar to infliximab. This suggests a potentially new treatment strategy for patients with inflammatory conditions.
This is exciting news as it shows that established drugs in one disease area could be repurposed to treat patients with very different diseases.
The authors highlight however that use of MEK inhibitors over the long term is associated with multiple side effects due to their role in a range of tissues. So, modification of the treatment will be needed e.g., development of novel delivery mechanisms to ensure they are delivered specifically to macrophages.
Questions for drug developers...
These results highlight a potential change in therapeutic strategy for patients with inflammatory conditions, by focusing in on the non-coding parts of the genome, inhibiting multiple cytokines and potentially repurposing drugs. This raises questions for drug developers in this area:
• How might the therapeutic positioning of our drug sit in this paradigm? Are we competitive?
• Have we broadened our drug discovery search to include parts of the non-coding genome?
• And, in particular for oncology drug companies, might any of the drugs in our portfolio be repurposed for inflammatory and immunological conditions? If so, what is the most efficient way to realise this value?
Contact
If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my email address dniven@nivenbiopharma.com . Feel free to also visit our professional website at www.nivenbiopharma.com for details on our services.
Please note, I have no conflicts of interest in the production of this article.
References
(1) A disease-associated gene desert directs macrophage inflammation through ETS2, Stankey et al, Nature, June 2024
