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Drug Discovery

Flagship launches Laronde to develop circular RNA therapies

The sequel to Moderna has ambitious plans to expand the use of mRNA

by Ryan Cross
May 10, 2021


A conceptual illustration of a ribosome translating a circular eRNA
Credit: Laronde
A ribosome turning the code of a circular eRNA into proteins

The pandemic has made mRNA part of our vocabulary. The rapidly developed and highly effective mRNA vaccines made by Moderna, Pfizer, and BioNTech have proven that mRNA can be used to prevent disease. And biotech investors are eager to see what’s next for mRNA, which can in theory be used to deliver the genetic code for any therapeutic protein or vaccine antigen into the body.

Now, one of the founders of Moderna is back with a sequel. Flagship Pioneering has launched Laronde to create a new kind of RNA therapy that is circular instead of linear—one it calls endless RNA, or eRNA for short. Flagship has committed $50 million to Laronde, whose name comes from the French for “round,” and set the audacious goal of creating 100 eRNA medicines within the next decade.

Laronde CEO Diego Miralles concedes that would have sounded ridiculous not long ago. “But now we have two mRNA vaccines designed, tested, approved, and administered to hundreds of millions of people in less than 18 months. So it is clear that we are entering a different world of programmable medicines,” he says.

Flagship began work on what would become Laronde in 2017. At the time, Avak Kahvejian, a general partner at the venture capital firm, noticed several new publications describing circular RNAs in mammalian cells. These RNAs, known as long noncoding RNAs, didn’t seem to contain instructions for making proteins. Some appeared important for regulating other genes, but the function and purpose of these strange molecules was largely a mystery. “Their biological function is quite unclear and is probably quite diverse,” Kahvejian says.

Kahvejian wondered whether Flagship could create circular RNAs that did encode proteins. The circular shape could have a number of theoretical advantages over the natural, linear form of mRNA. Circular RNA should be more resistant to exonucleases, enzymes that grab hold of the loose ends of linear mRNA and chop it up. The lack of free ends might also shield the circular RNA from innate immune system sensors and help avoid an immune response that can cause side effects and dampen the effectiveness of the therapy. Overall, the shape might lead to a better, longer-lasting drug than linear mRNA.

But ribosomes, the cellular machines that read the genetic code of mRNA and translate it into proteins, did not willingly interact with the circular RNAs. So Flagship scientists added a strand of genetic code called the internal ribosome entry site to make their eRNA attract ribosomes. Laronde’s eRNA sticks around for a longer time than mRNA, allowing cells to make therapeutic proteins for an extended period, but it is not permanent like gene therapy, Miralles says. The company hasn’t published or publicly shared any data about eRNA yet.

Laronde isn’t the only firm interested in circular RNA therapies. In February, a start-up called Orna Therapeutics launched with $80 million to develop circular RNA therapies that it has dubbed oRNA. Orna’s technology is based on work out of the lab of MIT’s Daniel Anderson, who has published a handful of papers describing the creation of circular RNAs and their ability to express proteins in cells.

None of these circular RNA therapies have been tested in humans, and Laronde isn’t even disclosing any particular programs or disease areas that it is focusing on yet. But Miralles says that the start-up is taking a wide view of the possible proteins it could encode in its eRNAs, including secreted peptides and proteins, antibodies, receptors, channels, enzymes, and more. Kahvejian says Laronde is exploring using its eRNAs for vaccines as well.

Given the intense demand for producing mRNA at scale during the pandemic, Laronde already has plans to build a manufacturing site that it is calling the eRNA Gigabase Factory—a nod to the Tesla Gigafactory created to support production of lithium ion batteries for the automaker’s electric vehicles.

Much like its predecessor Moderna, Laronde is on a fast trajectory, with plans to hire 200 people in the next 2 years. It would seem that Laronde’s eRNA can do everything that Moderna’s mRNA can do, and perhaps a bit more, but Laronde stops short of saying that it will replace Moderna.

“Moderna is an amazing company; we are standing on the shoulders of giants,” Miralles says. Kahvejian adds that he thinks there is room for both Moderna and Laronde to grow and coexist. “Obviously we have a deep relationship with Moderna,” Kahvejian says. “Moderna was aware and is aware of our existence, and we’ve been talking to them from the beginning.”



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