RNA editing: emerging from CRISPR’s shadow

Thorsten Stafforst remembers being told to stop wasting his time.

It was early last decade and scientists across the world were buzzing over a new tool, called CRISPR, that could precisely alter human DNA. Working in the German college town of Tubingen, Stafforst and fellow researchers at the local university were instead engrossed by the prospect of rewriting RNA, DNA’s chemical cousin.

“Everybody told me, ‘Why do you want to edit RNA?’” Stafforst said. “You can edit DNA now; that doesn’t make sense.”

Yet in 2012 they and, shortly afterwards, a group at the University of Puerto Rico figured out how to use a naturally occurring enzyme to swap out single “letters” in RNA sequences. Their discovery drew from research into the biology of octopuses and squids, which are adept at rewriting their own RNA. And as with CRISPR, the findings pointed to a novel way of treating disease. In a world newly enchanted by gene editing, however, their papers were met with far less acclaim.

More than a decade later, RNA editing is a fast growing corner of the biotechnology sector. About a dozen companies, from privately held startups to established biotech firms, are pursuing the technology. One already has early, but promising, clinical trial results. Others could follow soon. And large pharmaceutical companies, such as Eli Lilly, Roche and Novo Nordisk, have taken an interest.

RNA editing’s proponents say it may be safer and more flexible than DNA editing. Those advantages, they contend, will enable RNA editing to address more diseases, including common conditions that are now beyond genetic medicine’s reach.

“It has all the features of a technology that could leapfrog other editing technologies,” said Michael Ehlers, a general partner at Apple Tree Partners and the CEO of RNA editing startup Ascidian Therapeutics.

But RNA editing is far less tested than CRISPR, never mind other ways drugmakers already harness RNA to make medicines. Researchers and biotechs in the field aren’t yet sure whether RNA editing will work as intended, or whether it will prove as potent in humans as laboratory experiments have suggested. And one of the technology’s purported strengths may end up a flaw, as the transient nature of RNA editing’s effects could limit its benefit or force developers to administer it more often than desired.

Partly as a result, companies are testing out different approaches as they search for the best formula. “It’s still a very early technology,” Stafforst said. “We will have to learn how to make the best drugs, and that will take a while.”

Here’s where things stand:

What is RNA editing, and how does it work?

RNA molecules are shifty, versatile chains of nucleotides. While they can take different forms and hold various functions, their main job is helping cells turn the genetic information of DNA into proteins.

Sometimes, though, the final protein product looks different than the blueprint RNA translates. One way this occurs is by the work of enzymes that bind to RNA and switch one genetic letter for another. Those enzymes are named after what they do — adenosine deaminase that acts on RNA, or ADAR — and the changes they make can alter a protein’s shape or function. For instance, squids use ADARs to rewrite the expression of genes in their central nervous system.

Last decade, Stafforst’s group in Germany and then another led by Joshua Rosenthal, a senior scientist at the University of Chicago’s Marine Biological Laboratory, discovered how to co-opt this system. In separate research papers, they described ways to shepherd ADAR enzymes to a specific spot on messenger RNA molecules and change the transcription of the associated protein. Stafforst’s group and a team of Stanford University scientists led by Jin Billy Li followed up in 2019 with a paper outlining a simpler approach.

Their findings opened up new possibilities for drugmakers. A targeted RNA edit could correct the effects of a gene mutation that causes the production of a harmful protein, or boost levels of a protein that’s lacking. It could be used to mimic helpful genetic variants, break apart troublesome interactions between proteins or target conditions without a genetic component altogether.

“There’s a whole variety of different applications that are uniquely possible with RNA editing,” said Kris Elverum, CEO of Airna, a startup co-founded by Stafforst.

Biotechs are now attempting to prove they can turn that potential into medicines. Wave Life Sciences, one of the field’s leaders, uses strings of nucleotides to coax ADAR enzymes into making a specific edit. Its lead drug candidate, for an inherited disease called alpha-1 antitrypsin deficiency, or AATD, changes a letter on mRNA molecules, compelling the body to make a missing protein.

Other companies, like publicly traded ProQr Therapeutics and Korro Bio, as well as startups Airna, Shape Therapeutics and ADARx Pharmaceuticals, are pursuing similar ideas. “We’re all trying to get ADAR, this protein that sits inside of you, to actually make these edits very specifically, very safely, and not hit other adenosines throughout the RNA,” said Ron Hause, Shape’s senior vice president and head of AI.

There are differences in their approaches, though, ranging from the tools they use to screen for molecular guides, the RNAs they choose and the delivery methods they’re evaluating.

ProQr is trying to use its RNA editing therapies to induce the effect of variants known to protect against heart disease or to prevent toxic bile acid buildup in the liver. Korro is targeting AATD, as well as exploring how to correct for a troublesome genetic mutation in Parkinson’s disease. Shape is packaging ADAR enzymes into engineered viruses and sending them into the brain, where they could help treat neurological conditions.

There are other twists to the concept. Rather than try for single-letter changes, Amber Bio and Ascidian intend to rewrite whole stretches of RNA, akin to editing words or sentences in one go. Amber is using so-called Cas proteins — made famous with CRISPR — to make larger RNA edits. Ascidian, meanwhile, is editing “exons,” the sections of DNA that encode for proteins. It does so by using engineered molecules to replace a mutated exon with a functional version when DNA is converted into RNA.

These twists could allow RNA editing to be used for diseases caused by many different mutations rather than just one, or even broader groups of people with a particular condition. Ascidian’s first candidate, for a genetic eye condition called Stargardt disease, replaces more than 20 exons at a time.

Exon editing “really opens the aperture to a much broader patient population in any given genetic disorder,” said Ascidian Chief Scientific Officer Robert Bell.

What are the advantages over other technologies?

Gene editing research spread through biotech like wildfire over the past decade. A generation of biotech companies formed following the 2012 paper that first described the potential for CRISPR, a bacterial defense system, to be adapted to edit human genes. Since then, CRISPR science won a Nobel Prize, and a CRISPR drug for the blood diseases sickle cell and beta thalassemia reached market. Newer technologies like “prime” and “base” editing, designed to make more precise changes to DNA, have emerged, too.

CRISPR and its offshoots work by breaking DNA or rewriting genetic code — permanent changes that can carry unintended consequences. A wayward edit might disrupt the function of a healthy gene or, theoretically, turn cells cancerous down the road. That raises the bar for using gene editing, Stafforst argues. “You really need to have a fatal disease and a very bad prognosis,” he said. (Not everyone agrees, however.)

DNA editing therapies may also not be well suited for chronic conditions, or disorders for which people with the same underlying mutation experience variable symptoms or disease severity, said Korro CEO Ram Aiyar.

“You don’t know environmental factors. You don’t know what other genetic manifestations will lead to difference in severity, and you don’t want to find that out after you treat them with a one-time therapy and find out that it doesn’t really work,” Aiyar said.

RNA editing developers believe their technology can solve some of those problems. Mistakes caused by oligonucleotide-mediated editing should be able to be reversed without causing long-term harm. The transient effects of treatment would position drugmakers to treat acute conditions or to subtly dial protein expression up or down by adjusting dosing.

“It’s a class of new medicines that we can open up as a field,” said Wave CEO Paul Bolno.

Bolno’s company and others will build on the decades of work already done by makers of RNA-based therapies like antisense oligonucleotides and small interfering RNAs. Wave and ProQr are following a similar playbook, for example. Their treatments consist of specially engineered RNAs that enter liver cells with the help of a sugar molecule, not a microscopic virus or other substance the body may reject as foreign.

“We can take advantage of that history, but now apply it to the field of editing,” Bolno said.

Developers hope the end result is drugs with the power of gene editing, but that more closely resemble “traditional” drugs, said Elverum, Airna’s CEO.

“We’re all much more comfortable with medicines that can help us today, but give us the flexibility of being able to adjust based on how our health evolves in the future,” Elverum said. “It’ll take the word ‘editing’ and flip it on its head.”

Roadblocks remain, of course. Current ADAR-based approaches are only able to make a specific single-letter change in RNA, limiting their potential to such diseases that involve those letters. Drugmakers don’t yet know whether the edits they make will be efficient enough to produce a therapeutic benefit, how long that might last or if unexpected safety issues will crop up.

“The most important next step will be clinical proof that the modality, in principle, works,” Stafforst said in August.

Which companies are working on it?

At least 11 companies are developing therapies that edit RNA in one way or another.

Wave, which went public in 2015, has spent years working on multiple methods of RNA drugmaking. But in recent years it’s added RNA editing capabilities to its mix and formed an alliance with GSK.

ProQr made its Wall Street entry in 2014 and also recently made RNA editing a focus. The company was developing antisense oligonucleotides for eye diseases, but changed course after a clinical setback. It has a research partnership in place with Eli Lilly.

Korro, which was co-founded by Rosenthal, is a newer arrival on public markets. The company was formed a decade ago and raised more than $200 million from private investors before going public through a reverse merger in 2023. It’s working with Novo Nordisk. Beam Therapeutics, an established biotech in gene editing, is dabbling in RNA editing too.

Joining those companies are a new crop of startups.

Ascidian, which launched in 2022 with the backing of Apple Tree, already has a collaboration with Roche. It’s one of only a few companies, along with Wave and South Korea’s Rznomics, to start a clinical trial for an RNA editing drug.

Airna emerged from stealth in 2023 with $30 million in funding led by Arch Venture Partners. Like Wave and Korro, it is investing in AATD research. New Enterprise Associates, Decheng Capital and Breton Capital, among others, have poured nearly $150 million into Shape Therapeutics via two funding rounds. Shape is working on RNA editing therapies for the brain through a deal with Roche, according to Hause.

ADARx Pharmaceuticals is making drugs that can either silence or edit messenger RNA. It has 12 programs in development across genetic, cardiometabolic and central nervous system diseases, one of which is in clinical testing, according to its website. It hasn’t yet publicly disclosed an RNA editing program, however.

The field is still attracting new entrants. Radar Therapeutics emerged earlier this year with a $13 million seed round. Amber took in a $26 million seed round in 2023.

“I’m hoping all of us are successful, because we all go at it [from] a different direction,” said Korro CEO Aiyar. “A rising tide will raise all boats here.”

What is the status of the technology?

Wave gave RNA editing companies a boost last week. On Oct. 16, the company reported data from two people with AATD who were treated with one of its drugs in a clinical trial in the U.K. Treatment quickly produced significant amounts of a type of protein their bodies normally can’t make. The effects kicked in within days and lasted through about two months of follow-up. Importantly, no serious side effects were reported.

The findings are preliminary and don’t yet prove whether Wave’s therapy can safely and effectively treat AATD, an inherited disorder that causes lung and liver damage. Nonetheless, the data were the first clinical validation of RNA editing and were lauded by Wall Street analysts and investors as an indication of the technology’s potential.

“We view this as both a bar-clearing and, more importantly, enabling event for the ADAR space,” wrote Myles Minter, an analyst at the investment bank William Blair. Shares of Wave, ProQr and Korro all climbed substantially in response to the news.

It’s “an important milestone” and “a big win for the field,” said Korro’s Aiyar, of Wave’s results.

More details are expected later this month. They will be followed next year by results in people given more than one dose of Wave’s drug.

Other important readouts lay ahead. Ascidian should soon give a glimpse of exon editing’s potential. The company in June began enrolling people with Stargardt and other so-called ABCA4-related retinopathies in a Phase 1 trial. Ascidian will assess efficacy 12 to 18 months after dosing, according to a spokesperson, but isn’t specifying when those results might be available.

Rznomics’ drug, for liver and brain cancers, is in early-stage testing in South Korea as well.

By the end of 2024, Korro will apply to start a clinical trial in AATD, and expects to report interim results in the second half of next year. Its candidate is delivered via a tiny fatty sphere rather than the sugar molecule Wave uses. But it demonstrated an “improved preclinical profile” compared to Wave’s drug, wrote BMO Capital Markets analyst Kostas Biliouris, in a note to investors last week.

ProQr, meanwhile, plans to advance its first two RNA editing drugs into the clinic by early 2025.

Outside of its Roche partnership, Shape is advancing programs for Rett syndrome, Stargardt and AATD, according to Hause. It has a gene therapy-focused partnership with Otsuka Pharmaceutical, too.

And Airna could file papers to move into clinical testing with an AATD drug next year, according to Elverum, but hasn’t disclosed what else is in its pipeline.

As with initial efforts by CRISPR biotechs, many of these programs target the same diseases. And insiders believe the RNA editing field could undergo some of the same ups and downs as gene editing. Aiyar noted how every new technology goes through a hype cycle, when exuberance is followed by disillusionment and, later, a rebound that actually delivers workable products.

“There are folks that still really don’t know where RNA editing fits in the landscape,” he said.

While initial clinical data may “derisk” RNA editing, afterwards comes the work of making drugs that last longer, are more powerful and, eventually, solve thorny health problems. Stafforst, at the University of Tubingen, envisions a future when RNA editing will be used to adjust signaling cues in metabolism, opening up its use in treating heart and metabolic conditions.

“There’s still enough to do for the next 20 years,” he said.

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