The Next RNA Breakthrough? Maybe Bending Strands Into Circles

Investors flock to biotech startup Orna Therapeutics on the promise of low-cost treatment.

By Angelica LaVito

ILLUSTRATION: FATCHUROFI MUHAMMAD FOR BLOOMBERG BUSINESSWEEK

Less than two years ago, most people had never heard of mRNA. Then came the pandemic, and the scientific term became a household word. Now, Moderna Inc. and BioNTech SE are on the verge of selling more messenger RNA vaccines than any other drug product in the world.

The wild success of mRNA vaccines has prompted venture capitalists to pour huge sums into startups focusing on transforming straight RNA strands into circles. This simple-sounding but technically difficult feat would promise an alternative to the relatively short-lived power of mRNA, which sends instructions to cells to make specific proteins, such as the coronavirus spike for Covid‑19 vaccines. Delivering those messages via circles may produce a more stable, longer-lasting signal, potentially treating cancer, autoimmune disorders, and genetic diseases. Scientists at Orna Therapeutics Inc. in Cambridge, Mass., say they’ve figured out a way to do that by programming RNA with genetic code that instructs a line to split into several strands and then repair itself in the shape of a circle.

Unlike linear mRNA, circular RNA has no ends. That’s important, says Julia Salzman, an associate professor of biomedical data science and biochemistry at Stanford, because it makes material more resistant to enzymes in the body that break down mRNA. A straight line works for a vaccine, since it doesn’t need much time to elicit an immune response. But a straight line is a problem for therapies that need more time to work.

So far the idea of using circular RNA to create drugs remains theoretical. Nothing is proven yet, and none of the projects in development has been tested in humans. “It’s not immediately apparent to me this is the very best application of this technology without some other very sophisticated strategy to engineer this into the body,” says Carl Novina, a principal investigator of cancer immunology and virology at Dana-Farber Cancer Institute, adding that he’s yet to see convincing data supporting Orna’s approach. Orna says it’s up to the task and that the biggest opportunity for circular RNA is turning cells into cancer-fighting agents. Existing therapies called CAR-T, short for chimeric antigen receptor T cells, can already do this outside the body. That procedure requires drawing blood, isolating T cells, and genetically modifying them to attack cancer cells before reintroducing them back into the body. The process is time-consuming and costs about $500,000 for a single treatment. Orna says its circles could simplify treatment and lower the cost by getting the body to do all the work.

The idea of building circles from RNA strands has been around since at least 1995, when Peter Sarnow, now a Stanford professor, patented the technology. At the time, no one really knew what to do with the concept. In 2011, Salzman, then a researcher at Stanford, discovered naturally occurring circular RNA throughout the body. In the decade since, thousands of other scientists have studied the phenomenon. One of them is Daniel Anderson, a medical engineering professor at Massachusetts Institute of Technology, who’s a legend in the world of biotech thanks to his RNA expertise.

In 2016, Alex Wesselhoeft, a doctoral candidate in Anderson’s lab, was able to program RNA lines to cut themselves up and then come back together in the shape of a circle. “At some point,” Wesselhoeft says about the process, “it’s a little bit more of an art than a science.”

Research papers on the breakthrough written by Wesselhoeft and others in the lab caught the eye of Raffaella Squilloni, then finishing a fellowship at MIT and Harvard’s Broad Institute. Within 30 minutes over coffee at Starbucks, she and Wesselhoeft agreed to start a company. Anderson signed on. “When you look at the system the team has developed for making these things, it’s just an incredibly robust, straightforward scalable system that’s an order of magnitude cheaper than conventional modified RNA,” Anderson says.

Life sciences investment firm MPM Capital provided Orna with seed money. The company says it has raised more than $100 million from MPM and others. Orna hired biotech veteran Tom Barnes as its chief executive officer in 2020. The company wanted to differentiate its synthetic circles from those found naturally, so it dubbed them oRNA and decided to use the term for its name. “Bringing the cost down from many thousands of dollars to one that’s sustainable for larger markets will have a huge impact on patients,” says Ansbert Gadicke, co‑founder and managing director of MPM. That, at least, is the promise.