Most drugs target proteins in the cell, but the world of RNA has remained largely untapped by companies making chemical-based, or small-molecule drugs. That’s changing though—just in the last couple of years, there’s been a mini-boom in biotechs trying to overturn the long-held dogma that messenger RNA molecules (which carry the genetic instructions for proteins to the cell’s protein-making machinery) are undruggable.
The latest startup on this quest is Ribometrix out of Durham, NC, which today announced a $30 million Series A round of financing to fund the development of small molecule drugs targeting RNA involved in cancer and neurodegeneration. To do this, the company is studying the structures that RNA molecules form when they fold into themselves—think of a piece of string that gets crumpled up into a ball. These sorts of RNA structures are the kind that small molecules can grab onto. Figuring out the 3D structures of folded RNA (pictured) is critical to finding effective RNA-binding drugs, says CEO Mike Solomon.
To determine RNA structures, the company has taken technology from the research group of Kevin Weeks of University of North Carolina at Chapel Hill (UNC), and built it out into a drug development platform. The technology, called SHAPE, is a set of lab techniques and algorithms that allows researchers to probe and predict the 3D structure of RNA in cells, by locating the most bendy or flexible parts of an RNA molecule.
A research version of the SHAPE technology, which originated from Weeks’s lab at UNC, is publicly available and widely used by scientists in the RNA field, including those from competing drug companies.
But the SHAPE technology Ribometrix is using is an improved version of what’s out there publicly from UNC, says Weeks, who co-founded the company along with Katie Warner, Ribometrix’s research director. He adds that the startup has come up with its own bioinformatics software and other lab-based technologies, allowing Ribometrix scientists to find pockets in an RNA’s 3D structure that drugs can neatly fit into, and then to discover those drugs. The aim is for the drugs, once they bind to a disease-causing RNA molecule, to turn off the RNA’s biological function.
Weeks says the Ribometrix technology also allows his company to figure out not just if a small molecule is binding to an RNA, but also where. That, he says, is key to knowing whether the small molecule is disrupting the RNA’s function in the right way. “The ability to pinpoint where a small molecule is bound [on RNA] is important for turning a hit [an RNA-binding molecule] into a real therapeutic molecule,” Weeks says.
One competing company using the SHAPE techniques is Arrakis Therapeutics of Waltham, MA, which was founded in 2015 to develop small molecule drugs for RNA. Arrakis has also expanded the SHAPE technology and built its own bioinformatics software and other tools around it for drug discovery, says Jennifer Petter, Arrakis’s founder and chief scientific officer. “We are heavy users of SHAPE and related technologies,” Petter says. “Kevin [Weeks]’s work [in developing the SHAPE technology] is an important contribution to the RNA field.”
Both Ribometrix and Arrakis are going after drug targets in cancer and neurology. Solomon, Ribometrix’s CEO, says his company has been doing drug development for about a year since it got its seed funding. It has also picked targets, including c-myc, a famous cancer gene that has long been thought undruggable. The company is also pursuing a target in Huntington’s disease.
The growing number of companies working on small molecules for RNA reflects several key advantages of these kinds of drugs. For one, they are taken in pill form. Other RNA-targeting strategies such as RNA interference require additional technologies or injections to get the medicines to the targeted tissues.
But the arrival of all these RNA-targeting startups is also making it harder to differentiate between them. Weeks says Ribometrix is focused solely on RNA molecules that form “higher-order” 3D structures—this happens when relatively simple 2D RNA structures then fold onto themselves again and again to generate something more complex and three-dimensional. Not all RNA molecules do this, he says, but those that do form the kinds of pockets that a small molecule should fit into in a specific and predictable way, Weeks says.
Another company that launched earlier this year, San Diego-based Expansion Therapeutics, is also developing small molecules for RNA, and is homing in on different kinds of RNA structures formed by specific mutations that underlie a set of rare genetic diseases.
Other startups that have gotten off the ground in the last couple of years—Skyhawk Therapeutics, Accent Therapeutics and Gotham Therapeutics—are targeting other aspects of RNA biology with small molecules.
Petter of Arrakis says her team is also figuring out RNA structure—using sequence data—and then linking structural information to the function of an RNA, all while building new tools to do this “at scale”.
Solomon says Ribometrix, now with 15 employees, will double in size over the next year with the new funding.
The Series A round was led by M Ventures, with new investors Amgen Ventures, Pappas Capital, and Illumina Ventures joining in. Ribometrix’s founding investors SV Health Investors, AbbVie Ventures, Hatteras Venture Partners, MP Healthcare Venture Management, the Dementia Discovery Fund and Alexandria Venture Investments were also part of the round.