Despite the vastness of the human genome, drug discoverers focus mostly on exploring less than 2% of its landscape—the small fraction that encodes instructions for making proteins. The remaining 98% is sometimes dismissed as junk DNA. Other times it’s dubbed the dark matter of the genome, connoting unknown function but potential importance.
Some scientists, including Benjamin Greenbaum, a computational biologist at Memorial Sloan Kettering Cancer Center, and David Ting, a clinical oncologist at Massachusetts General Hospital Cancer Center, have used new tools to sequence and analyze this dark matter. And they say it may be more important for health and disease than previously thought. Now they’ve got a new company and financial backing to put that hypothesis to the test.
Cambridge, Massachusetts–based start-up Rome Therapeutics has launched with $50 million in series A financing from GV, Arch Venture Partners, and Partners Innovation Fund. The start-up is led by cofounder and serial entrepreneur Rosana Kapeller.
It’s Kapeller’s third company. She previously cofounded the cancer biopharmaceutical firm Aileron Therapeutics and the computational chemistry biotech Nimbus Therapeutics—where she spent 8 years as chief scientific officer until 2018. After a sabbatical, she joined GV, formerly Google Ventures, where she incubated Rome Therapeutics.
Rome is focused on a section of the genomic dark matter comprised of repetitive DNA. Called the repeatome, this slice makes up 60% of the entire genome. Much of this mysterious region is thought to derive from viruses that embedded in our DNA millions of years ago. In healthy cells, DNA of the repeatome is tightly packed and silent. But when cells are stressed or sick, this repetitive DNA can unfold, causing the cell to transcribe it into RNA.
Normally, this RNA triggers the alarms of the innate immune system and prompts the sick cell to die. In cancer cells, it’s a different story.
“Cancer cells can co-opt this whole mechanism and turn it on its head,” Kapeller says. Scientists have discovered that cancer cells make large amounts of repeatome-derived RNA without triggering the innate immune system’s alarms. Enzymes inside cancer cells called reverse transcriptases grab hold of this RNA, turn it back into DNA, and then integrate the DNA into the genome. It’s strikingly similar to a viral life cycle, Kapeller explains.
Greenbaum and Ting have discovered a way to stop this process, boost the immune response, and leave cancer cells more vulnerable. Antiretroviral drugs known as nucleoside reverse transcriptase inhibitors (NRTIs) can block reverse transcriptase. Ting and Greenbaum have used the NRTI lamivudine, a commercial AIDS treatment, on colorectal cancer cells in a dish and in mice and found that it had “anti-cancer effects,” according to a grant from the US National Institutes of Health. They’ve also tested the drug in a small study of 20 people with colorectal cancer and are planning further studies.
“It is a whole new uncharted territory, and that’s what attracted me to it,” Kapeller says. But since these repeatome-derived RNAs act like viruses, she says her company can take a page from “the antiviral therapy playbook” as a starting point for finding new drugs that modulate the repeatome.
Rome isn’t disclosing its drug targets yet, although Kapeller emphasizes that the start-up is not solely focused on reverse transcriptase. Rome is looking at all enzymes that cancer cells use to turn RNA back into DNA, including proteases and integrases. The firm is focusing on small-molecule drug discovery for now, although this could expand in the future, she adds.
To treat cancer, Rome will need to design molecules that keep the repeatome-derived RNA around and have the end result of boosting the innate immune system. Rome is also working on drugs for autoimmune diseases, with the goal of designing molecules that prevent activation of the innate immune system. In the future, the firm’s repeatome-based drug discovery could also be applied to infectious diseases, neurodegenerative diseases, and other age-related conditions, Kapeller says.
“It is wild, and that’s what I love about it,” Kapeller says. “I always say, ‘Give me the hardest problem in biology to solve.’ ”.