The Biology of Repeats
Repetitive sequences (“repeats”) derived from ancient viral infections have been integrated into human chromosomal DNA throughout evolution. When we’re healthy, these repeats lie dormant. However, repeats are activated when the cell is stressed or diseased. Once activated, these internal repeats are recognized by the immune system in much the same way as external viruses are recognized. This triggers viral mimicry responses that alert the body to eliminate stressed cells and repair damaged tissues.
Activated repeats are transcribed into RNA and can then be reverse transcribed into RNA:DNA hybrids and double-stranded repeat DNAs which stimulate a variety of RNA and DNA sensors to awaken the immune system. Specific repeats that encode for reverse transcriptases, which we refer to as Endogenous Reverse Transcriptases (eRTs), control this process.
There are many other ways in which repeats influence human biology. For instance, when certain mobile repeats are activated in cancer cells, they are copied and pasted into new locations in the genome, leading to genomic instability associated with aggressive metastatic tumors. Cancer-specific expression of repeat-encoded proteins generates tumor neoepitopes that elicit anti-tumor adaptive immune responses. Each node of repeatome biology represents an opportunity for new therapeutic intervention.
Repeats and autoimmune disease
What goes wrong
Chronic activation of repeats overstimulates the immune system, which leads to the inflammation and chronic pain that is characteristic of autoimmune disease. Innate immune sensors are critical for driving these pathological responses.
Repeats and cancer
What goes wrong
Initially, cancer cells are held in check by activation of repeat-mediated viral mimicry responses. However, cancer cells can acquire mutations that enable them to tolerate repeats and evade these responses. Expression of mobile repeats that can re-integrate into the genome, such as LINE-1, leads to genomic instability and genetic evolution.
Our treatment approach
Our treatment approach
Endogenous reverse transcriptase inhibitors (eRTIs) block the reverse transcription of repeat RNA into DNA.
In autoimmune disease, this reduces activation of DNA sensor pathways, decreasing production of pro-inflammatory mediators and thereby attenuating the autoimmune response.
In cancer, eRT inhibition blocks the reintegration of cDNA into the genome, decreasing genomic instability and evolution.
Repeatomics platform for drug discovery and precision medicine
Because the repeatome makes up more than 50% of the human genome, there are huge quantities of data which – until recently – were underexplored.
Genomic profiling of repeat expression patterns in patients is opening up a powerful new window for precision medicine. ROME is building proprietary data science tools to fully leverage the power of repeatomics.
Through this, we will be able to identify disease, inform prognosis, predict response to existing therapies and define patient subsets likely to respond to novel repeat-targeted therapies.
Our pipeline
We are working to develop therapies that target the repeatome in order to treat a variety of conditions across oncology and autoimmune disease. Our pipeline includes multiple discovery programs.
Our call to action is clear
As a community, we have made significant progress against serious conditions like cancer and autoimmune disease, yet there are still far too many patients who do not respond to any therapy or only derive short-term benefit.
That’s not good enough.
At ROME, our mission is to drive even the most intractable cancers and autoimmune diseases into sustained remission. We take as our model the advances made in treating HIV, diabetes and cardiovascular disease. Replicating this success is wildly ambitious — but we believe it is within our reach. The repeatome points the way.