Unlocking the Power of RNA, Part 2

In the second feature on CircNova, CSO Joe DeAngelo explains the science behind the company and why he thinks their technology can unlock the power of RNA to drug targets that have previously been undruggable.

Companies to Watch – CircNova

by Marie Daghlian

CircNova believes circular RNA has great potential benefit for therapeutic development by extending the range of clinical targets that can be drugged.

Currently most drugs are developed by targeting proteins either using small molecules as inhibitors of enzymes, or biologics like antibodies to bind and inactivate proteins. The numbers vary but only between two and 20 percent of clinical targets are druggable, claims Chief Scientific Officer Joe DeAngelo. The rest is undruggable because of the modalities used.

“Now, once we start moving into non-coding RNA, the druggable universe becomes huge, and that 80 percent of undruggable suddenly becomes druggable. So that’s why this is really kind of the future of medicine,” he says. “What we need to do is expand the number of targets, and the target universe is expanded by going after targets that can be drugged with non-coding RNAs.”

In order to do that, the company is building an AI-enabled platform, the NovaEngine, to generate RNA structures that enable AI-generated design of RNA with specific activities using proprietary methods to produce, test, stabilize, validate, and deliver circRNA with druggable features.

This means focusing on non-coding circular RNA. “That’s really the gist of CircNova,” says Chief Scientific Officer Joe DeAngelo. “Circular RNA is incredibly interesting.”

Unlike messenger RNAs (mRNAs), which get degraded quickly and have had some therapeutic success, especially in vaccine development, circular RNA is fairly stable and so useful for clinical indications where you want the therapeutic to stick around.

“Circular RNA can have any kind of sequence you want, so it can have a messenger, but it’s in a circle. It does not have an end. It doesn’t have a five prime end. It doesn’t have a three prime end. And that’s the way linear messenger RNA is degraded. It’s degraded from the ends. So circular RNA has no ends. It’s much more stable. It lasts a lot longer,” says DeAngelo.

Circular RNA can also deliver non-coding RNAs. Linear RNA like mRNA is useful only for delivering message, but circular RNA is more stable, and also has greater modalities in terms of what you can deliver with it. That’s where non-coding RNAs come in. DeAngelo says that if you think about RNA in general, mRNA is a very small portion of total RNA with about 2 percent of the human genome actually coding for mRNA.

“What does the rest do? Well, everything else used to be junk,” DeAngelo says. “But it turns out that of all the RNA that’s transcribed from DNA, 75 percent is non-coding. And now we’re beginning to find out it has all sorts of functions.”

One of the major functions of non-coding RNA is micro RNA (miRNA), and related to miRNA is small interfering RNA (siRNA). And then also you could add in antisense RNA. And what they do is control mRNAs.

For example, miRNA is a non-coding RNA that can bind to specific sites in mRNA and cause it to be degraded, an epigenetic control mechanism that exists in non-coding RNA and are one class of non-coding RNA that have great potential for therapeutic application. Another type of non-coding RNA is what are called sponges that actually bind and inactivate miRNA and prevent it from degrading mRNA.

“That’s kind of the yin yang of it,” says DeAngelo. “You have micro RNA that can degrade messenger RNA, and then you have micro RNA sponges that can inactivate the micro RNA and prevent the degradation of messenger RNAs. So, you can control protein synthesis post transcriptionally after the messenger has been made. You can either prevent it from being degraded and extend its life, or you can cause it to be degraded. And that’s all done with non-coding RNAs.”

Circular RNAs are able to deliver any modality of non-coding RNA, be it mRNA, miRNA, or siRNA

That’s where CircNova comes in—expanding the target universe by going after targets that can be drugged with non-coding RNAs—first by using circular RNAs, which are stable, last longer, are easier to deliver, and also able to deliver any modality of non-coding RNA, be it mRNA, miRNA, or siRNA. They can deliver miRNAs, they can deliver siRNAs. They can deliver antisense RNA, they can deliver miRNA sponges, they can deliver RNA-binding protein sponges.

“There’s a huge breadth of targets that are now open to development using this sort of technology. Now we’re trying to bring these two things together, and it is a novel field,” DeAngelo says. “One of the interesting things about non-coding RNAs is that suddenly the RNA structure becomes important.”

Non-coding RNA is like a protein. It has an active structure and the tertiary structure of non-coding RNAs becomes important in their function and that is why CircNova is developing an AI engine to be able to determine structure, sequence structure, relationships related to specific activities.

“This is the real challenge that we face in the non-coding RNA space,” says DeAngelo. “And it’s one of the reasons why everybody’s working on messenger RNA because it has a linear sequence. But you have to think beyond just the sequence. The sequence is still important and informs the structure, but the structure is determined by non-covalent forces, such as ionic forces or hydrogen bonding forces. And so now we need to advance our understanding of structure. CircNova’s goal is to use new circular RNA as a delivery mechanism, focus on non-coding RNAs and use structure sequence relationships to determine how to target specific classically non-druggable targets.”

The company is talking to a lot of potential investors and has attracted a lot of attention from seed stage venture and angel investors. DeAngelo is CircNova’s scientific founder but is not an academic. His background is in yeast biology and synthetic biology. He says the company is going to use a lot of yeast systems for making circular RNAs, designing different backbones and structures, all of which has attracted academic interest. In fact, CircNova is in talks with universities for complementary technologies for in-licensing and is open-minded in terms of relationships, even looking to universities to be founders.

DeAngelo says that as far as narrowing the universe of targets, the company’s disease focus will first be in oncology and neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s, and ALS.

“There are interesting relationships between cancer and neurodegenerative diseases,” says DeAngelo. “For example, cancer cells protect themselves from being killed by mechanisms that actually kill neurons in neurodegenerative disease. In cancer, you want to be able to prevent the cancer cell from protecting itself from these mechanisms of action, and in neurons, you want to be able to protect them from these mechanisms that kill cells. And by working on the two in parallel, we can go in both directions. And if we can figure out how to turn one on, we can also figure out how to turn it off.”

Finally, CircNova plans to build itself out as a DEI company. Between trying to diversify the industry and advance a new modality in therapeutic development, CircNova sits at the cusp of a new frontier. “I really think circular non-coding RNA is the future,” DeAngelo says. “It’s really exciting and there’s a lot of interest from investors.”


This is part 2 of the Big4Bio Company to Watch program for September 2023: CircNova
For more information on the series, click here.