Plumbing the repeatome to find new cancer targets
CEO, co-founder, president: Rosana Kapeller, Ph.D.
Co-founders: Benjamin Greenbaum, Ph.D. and David Ting, M.D.
Based: Cambridge, Massachusetts
Clinical focus: Creating drugs for targets in 60% of the genome previously dismissed as “junk DNA”
The scoop: Rome Therapeutics aims to drive chronic diseases into sustained remission by drugging targets that were previously dismissed as “junk DNA.” It is developing drugs that go beyond the 2% of the genome that codes directly for proteins and focusing on parts of the genome called the repeatome, which is made up of repeating sequences of nucleic acids, called repeats for short.
What makes Rome fierce: Rome is working on new treatments for cancer and autoimmune conditions inspired by advances in the treatment of other chronic diseases, such as HIV, diabetes and heart disease. It’s doing so by plumbing the repeatome for new drug targets that have been out of reach—at least, until recently, thanks to advances in technology.
But it isn’t just new technology that enables Rome to go after this uncharted territory.
“The way we think about things is different today than it was 10 years ago, so it’s also the mindset,” said Rome co-founder David Ting, M.D., associate clinical director for innovation at Massachusetts General Hospital Cancer Center. “So, it takes technology and tools, but also the prepared mind. And we are prepared.”
Repeating sequences make up 60% of the human genome, but scientists and drug developers have long dismissed them because they don’t code directly for proteins. Instead, they have zeroed in on the 2% of the genome that does code for proteins.
“Those sequences are translated into mRNA that codes for proteins, and those proteins are drug targets,” said Rome CEO Rosana Kapeller, Ph.D.
Rome believes that looking beyond that low-hanging fruit could yield targets for longer-lasting treatments for cancer and autoimmune disease.
As technology progressed, scientists began to understand the role of repeats and that RNA has functions beyond just coding for proteins, Kapeller said. Many of those repeats, it turns out, come from ancient viruses that have become integrated into human DNA over hundreds of millions of years.
Benjamin Greenbaum, Ph.D., another Rome co-founder, discovered that these virus-like sequences get transcribed into RNA that looks a lot like viral RNA, triggering an immune response.
Repeats generally stay dormant, “waking up” and transcribing into RNA only when cells undergo stress. This virus-like RNA switches on the innate immune system to remove damaged cells, which then sends the repeats back into hibernation.
In cancer, this process kicks in as cells go from healthy to malignant. The virus-like RNA calls forth an immune response to kill cancer cells. However, cancer cells can evade this process by modifying the RNA into DNA that they incorporate into their own genome. By tamping down on the RNA, the cancer quiets the alarm bells and evades the immune system so it can grow.
Repeats also play a role in infections, autoimmune disease and neurodegeneration. Rome is looking for ways to adjust the function of those repeats and activate—or inactivate—the innate immune system, depending on the disease, Kapeller said.
“That’s why we are fierce—we took an area of biology that everybody was kind of avoiding for a while and a variety of reasons, including the technology not being available to explore that biology,” she added. “We are not only going to explore that biology, but we are going to make drugs based on that knowledge.”
Rome launched in April this year with $50 million toward that mission. It’s keeping its targets under wraps, but Kapeller divulged that it’s starting to identify chemical matter for a couple of discovery programs in cancer and autoimmune disease. If all goes to plan, it will have a development candidate in the next couple of years. Down the line, Rome will look into partnering as the repeatome is a “very large arena” for one company to take on alone.
At about 12 full-timers, the team is lean and mean—and about 80% women, by Kapeller’s count. That wasn’t by design, she says: “It was all about hiring the right people for the job.”
The right people include staffers across various disciplines, from clinical oncology and cancer biology to physics, statistics and computational drug design. Rome hopes to grow to about 15 by the end of the year.
Investors: Arch Venture Partners, GV, Partners Innovation Fund