At one end of the drug development table are people like Uli Stilz, PhD, a former vice president at Novo Nordisk and founder of the Danish company’s Bio Innovation Hub in Boston. Stilz has worked on several drugs for various conditions and modalities. Novo Nordisk has many tools at its disposal, including small molecules, siRNAs, antibodies, cell therapies, and more. However, the global health company still lacks the key to unlocking the mysteries of cardiometabolic diseases.
“How can we develop new therapeutics with transformative potential that are not accessible or where the biology would be locked?” Stilz told Inside Precision Medicine. “We want to unlock new biology.”
On the other end of the table are people like Ram Aiyar, PhD, founder of seven startups, the most recent of which is RNA editing company Korro Bio, who are eager to introduce new technological flavors. However, developing a potential next-generation medicine is one thing; obtaining all necessary funding, tools, personnel, and infrastructure is another.
“There are some areas that we can move forward with as a small company, and there are others that we can’t,” said Aiyar.
Though Stilz and Aiyar are at opposite ends of the biopharma spectrum, they both believe that you must form partnerships if you truly want to enable the production of medicines. Aiyar and Stilz have been working to combine Korro’s proprietary platform for developing RNA-editing medicines with Novo’s extensive knowledge and drug development experience in cardiometabolic disease.
“What we bring to the table is going after targets in a very novel fashion that Novo Nordisk has experience in, but I don’t think that term exists anymore, given all the new technologies coming together,” Aiyar said.
“Korro brings a unique platform and capability, message RNA editing, and we add this deep cardiometabolic insight, potentially unlocking some targets that are not unlocked today,” Stilz said.
These reciprocal responses show the companies’ trust and investment in each other. This week, the two organizations formally announced their intention to work together to find and develop new genetic medicines to treat cardiometabolic diseases. The partnership uses Korro’s OPERA platform to make oligonucleotide-directed RNA edits to two unknown targets, first for cardiometabolic diseases.
Korro’s total deal value is up to $530 million in upfront, development, commercial milestone payments, tiered royalties, and R&D funding.
The RNA editing palette
Over the past few decades, researchers have developed several proven approaches for modulating protein expression and activity. However, achieving precise control over a protein in a tunable and temporally refined manner has been tricky. RNA editing changes that equation.
RNA editing, like siRNA, works by co-opting endogenous enzymes and RNA-binding proteins to affect a single nucleotide change—in this case, from adenosine to inosine. For siRNAs, the co-opted argonaut and dicer proteins can cleave RNAs. The co-opted proteins for RNA editing come from a highly conserved group of enzymes known as the adenosine deaminase acting on RNA (ADAR) family, which mediates the adenosine-inosine reaction.
Korro’s OPERA RNA editing platform uses chemistry and machine learning to create therapeutic oligonucleotides. These are called CHORDS (customized high-fidelity oligonucleotides for RNA deamination), and they bring ADAR to a specific adenosine by making a double-stranded RNA structure. With a single adenosine to inosine change, RNA editing can modify 12 amino acid sequences, opening the door to some novel ways to alter proteins.
“Achieving specificity—making a single change and either stabilizing the protein, activating a transcription factor, or modulating its function based on structure-function relationships—transiently has never been possible before, until now,” Aiyar said.
For example, lysine post-translational modifications (PTMs) provide a wide range of reversible changes to proteins—stability, interactions, activity, localization, expression, processing, and degradation—which can regulate many cellular processes.
“Picture this: there are E3 ligases that bind lysines and then start degrading those proteins. If you remove that lysine and convert it to an arginine, you have no ubiquitination—or, for that matter, acetylation and phosphorylation,” said Aiyar. “There are these fundamental intracellular processes that you can go after. You can identify point variants and demonstrate a protein’s stabilization, acetylation, or phosphorylation. Those are areas I think could be intriguing for us.”
Compared to DNA editing, RNA editing has many benefits regarding safety. RNA editing enables titratable and reversible therapy because these changes occur in the RNA, not the genome. Another difference is that the ADAR system does not make microRNAs like siRNAs do. This means that the off-target effects and safety profiles for editing RNA are very different. “We don’t generate debris—we only generate modified protein,” said Aiyar. “That’s very beneficial for us.”
Deliverable, titratable pharmacology
Since Korro’s platform solves the RNA sequences that can drive RNA editing, two main obstacles remain: manufacturing and deliverability. RNA editing ultimately comes down to oligonucleotide manufacturing, which is very straightforward and already has precedent for generating clinical-grade compounds, so there’s not much for Korro and Novo to worry about in that department.
The delivery side of things may present a bit more of a challenge. Since the focus will be on cardiometabolic diseases, the liver will be Korro and Novo Nordisk’s main target. But even there, Novo has much experience from its siRNA work, which uses the N-acetylgalactosamine (GalNAc) conjugation technique for getting siRNAs into liver cells.
“We found and discovered GalNAc in the liver and hepatocytes, and I am confident that we will find similar receptors in other cell types,” Stilz said. “We are already working on this as a community, and as time goes on, we will unlock more and more cell types, which may speak to what we cannot do right now. We have yet to unlock all of the cell types we want, so we have a long scientific journey ahead of us. But we will start with things we can do today.”
Aiyar said that other companies have developed technology to deliver small RNAs to various targets, including skeletal muscle, lung, adipose tissue, and immune cells.
Altogether, this is precisely the pharmacologically titrated platform Stilz has been waiting for to make a real impact in the chronic disease space.
“Here is a platform that we believe can enable and unlock biology in ways that no other tools do today,” said Stilz. “We all know we lack a tool to introduce biologics, antibodies, or proteins into cells. However, we now have a tool that enables us to modulate intercellular biology using an oligonucleotide. We know from the siRNA field that this oligonucleotide is scalable and has a significant safety precedent in the marketplace, with many people already using it.”
Aiyar concurs with Stilz that the initial focus of RNA editing should not be on rare Mendelian diseases because the small patient populations mean a market opportunity on the smaller end of the scale. There’s much bigger fish to fry that RNA editing can cook up than DNA editing cannot.
“Uli and I are firm believers in science and the innovation process, and [DNA editing] will get there,” Aiyar explained. “It may not be today; it could be in 20 years. But Uli and I want to develop drugs today. We need to concentrate on areas where RNA editing can be most effective. We are here to solve big health problems, and this oligonucleotide is safe, titratable, and specific. I believe that in four years, between our pipeline and the one that we co-develop together, we will better understand the possibilities in the clinic.”
