Multiple companies aim to surmount the limitations of CAR-T therapy by going beyond T cells and engineering cell therapies based on natural killer (NK) cells or macrophages instead. Orna Therapeutics’ solution is more holistic: bringing CARs directly to a patient’s immune cells to help them kill cancer. The company uncloaks with $100 million to develop this approach, among others, all of which are based on engineered circular RNA.
(Orna Therapeutics)
Dubbed oRNAs to differentiate them from naturally occurring circular RNAs, the company’s approach is based on research out of MIT by Alex Wesselhoeft, Ph.D. and professor Dan Anderson, Ph.D. Unlike messenger RNAs (mRNAs), which are linear, circular RNAs are—of course—circles, closed with a covalent bond. It’s a shape that gives them several advantages over the mRNAs that form the backbone of treatments such as some COVID-19 vaccines, as well as over immune therapy approaches like CAR-T.
“The advantages over linear RNA are really in three areas: production, delivery and performance,” said Orna CEO Tom Barnes, Ph.D., who takes over from interim CEO Shinichiro Fuse, Ph.D., a managing director at MPM Capital, the venture firm that seeded and incubated Orna.
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“A circle, maybe counterintuitively, is not more complicated to make than a line,” Barnes said. The way Orna has designed them, the circles form during transcription reactions, the process where a DNA sequence is copied to make an RNA molecule.
“Every circle is full-length, with the same sequence. With linear RNA, it is always a problem to figure out if you have a full-length species,” Barnes said. What's more, making linear RNA needs extra steps like adding cap and tail structures, which tell ribosomes where to start translating the RNA and help the RNA keep stable. Without those extra steps, Orna can work with larger, longer RNAs which tend to be more fragile and harder to handle.
As for delivery, Orna can pack more oRNAs into a lipid nanoparticle than linear RNAs, chiefly because they can fold into 3D structures without tails getting in the way.
(Orna Therapeutics)
“Because they’re more compact, they play nicer with different lipids, so there is a broader set of lipid formulation options than you might have with an mRNA,” Barnes said.
The enhanced capacity of these circles creates room for other genes, such as those that code for cytokines, to boost the immune response in the tumor microenvironment, said Greg Motz, Ph.D., Orna's vice president of biology.
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Wesselhoeft and his MIT colleagues figured out how to make oRNAs express proteins despite not having a cap for ribosomes to latch onto, a means of expression that can result in much higher levels of protein than a linear RNA could, Barnes said. Coupled with greater persistence in the body, oRNAs could mean giving patients a smaller dose to get the desired treatment effect or opening up disease areas that require very high protein expression levels and have been out of the reach of linear RNA-based treatments.
Orna spent its time under the radar developing the delivery vehicles for its oRNAs, landing on two major targets: liver cells and immune cells. The hope with its immune cell-targeted research is to develop a cell-like therapy that doesn’t require removing a patient’s cells, engineering them and putting them back in.
“Ours would be a pharmaceutical-type product that would be safer and re-dosable. We might be able to get all the benefits you have with cell therapy, but without a lot of the downside,” Barnes said.
The company’s launch coincides with an $80 million series A round from MPM, Taiho Ventures, F2 Ventures and the PAGS Group along with several Big Pharma players: Bristol Myers Squibb, Novartis Institutes for BioMedical Research, Astellas Venture Management and Gilead’s Kite unit.
“We think the money can bring us to the doorstep of the clinic and what we’re doing this year, pushing out to build our pipeline with immunotropic lipids and liver-tropic lipids,” Barnes said.