With the modality now in early clinical trials, experts say more efficiency, broader editing capabilities and delivery breakthroughs are needed to propel RNA editing to the next stage.
Potentially safer and more flexible than DNA editing, RNA editing has made important strides during the last decade. In 2024, the field inched further forward, with Wave Life Sciences announcing the first-ever results from the mechanism in humans, and experts are predicting even more extensive progress in 2025.
RNA editing “was clearly a niche, or almost really non-existent 15 years ago . . . and it has not only started existing but gathered a lot of momentum,” Silvi Rouskin, an assistant professor of microbiology at Harvard Medical School, told BioSpace.
Dan Rosan, chief financial and business officer at RNA-focused Ascidian therapeutics, agreed, telling BioSpace “it’s been really incredible to see RNA editing evolve so quickly.”
“Obviously, the use of RNA as an intervention was kickstarted by the vaccine technologies a couple years ago, and now we’re really seeing that manipulating RNA in vivo has both the potential for a lot of therapeutic effect and also seems to have some distinct advantages over DNA editing in vivo.”
Rosan pointed to a “flurry” of new clinical trials launched by Wave and Korro Bio in alpha-1 antitrypsin deficiency (AATD)—a genetic condition that can cause lung and liver damage—and Ascidian in Stargardt disease, an inherited single-gene retinal disorder.
“We’re starting to prove out the hypothesis that it’s therapeutically powerful to edit RNA, and we’re seeing that the level of regulatory comfort with RNA editing really seems to be there,” he said. Rosan added that regulators in fact seem “much more comfortable” with RNA editing than with its cousin, DNA editing.
“If you edit DNA incorrectly, that is a binary edit that will be present forever in the patient,” he said. “But RNA is a transient model, so it’s just much more forgiving of any unintended editing effects.”
A Decade of Progress
RNA editing—as with many therapeutic modalities—has been slow to develop but has picked up steam in the past 10 years as new editing capabilities have emerged.
Early in the last decade, scientists at the University of Tübingen and the University of Puerto Rico separately discovered that they could use a naturally occurring enzyme called adenosine deaminase acting on RNA (ADAR) to swap out single bases in RNA sequences. Then, in 2017, scientists figured out how to fuse CRISPR-Cas13 with ADAR using a replacement technology called REPAIR, which can convert adenosine to a biological mimic of guanosine known as inosine. This was important because there are some genetic diseases in which changing adenosine to guanosine “will make a huge difference,” Rouskin said.
Two years later, another RNA editing tool called RESCUE enabled the conversion of cytidine to uridine. “So you’re expanding your toolbox, which is exciting,” Rouskin added.
As RNA editing has matured, there was a lot of reflection regarding the first therapeutic target. Rosan said the space has largely succeeded in selecting indications where RNA editing is distinctly advantaged. “It’s a molecular biology question more than a therapeutic area question,” he explained. “What are the characteristics of the genetic defect that lend itself to this form of editing?”
For Wave, that meant AATD, Paul Bolno, president and CEO, told BioSpace. The most common cause of the disease is a guanosine-to-adenosine point mutation in the SERPINA1 gene, and Bolno felt RNA editing could differentiate itself from other modalities such as siRNA and antisense oligonucleotides in this space. It just “made a lot of sense,” he said.
In October 2024, Wave presented data from WVE-006 in AATD demonstrating that a single dose caused AAT levels in the blood to rise. At the lowest dose, “we’re basically achieving nearly therapeutic levels of editing,” Bolno said. Multi-dose data are expected this year.
Bolno highlighted RNA editing’s potential in upregulation, where it could treat disease by increasing the expression of a protein that could be mutation agnostic. He pointed to cholesterol lowering as one area where this approach could be particularly useful.
“The holy grail for [lower cholesterol] has always been if you could increase the density of receptors on the surface, then you could actually treat the underlying disease,” Bolno said, adding that the way to do this is through upregulation. Stabilizing the transcript with RNA editing increases copy numbers, which translates to increased expression of LDL receptors, he explained.
Another opportunity for RNA editing, Bolno pointed out, is delivery to targets outside the liver, which editing technologies have traditionally targeted because that organ metabolizes all foreign particles. “We’re making meaningful progress on extra-hepatic applications for editing,” such as in cystic fibrosis and MECP2 duplication syndrome, he said.
These advances are opening up a much larger potential patient population that could be helped by RNA editing, Bolno said. “The approaches that we’re bringing forward behind AATD now address collectively over 10 million patients.”
Looking ahead to 2025, Bolno predicted further progress across these applications. “Then, we could really open up and blow out the field for RNA editing,” he said.
Overcoming Challenges
For all the progress that has been made over the past decade in RNA editing, experts agree that there are still challenges that need to be overcome.
One hurdle is inefficiency, Rouskin said. “Ideally, you want to edit 100% of all your molecules that are in a specific cell,” but currently, only around 2% of these molecules can be edited. This is an area in which Ascidian “has shined tremendously,” said Rouskin, who is consulting with the biotech, “because they had a really high level of RNA editing.”
In January 2024, Ascidian’s ACDN-01 became the first RNA exon editor to enter clinical development when the FDA approved the company’s investigational new drug application. ACDN-01 is also the only candidate currently in clinical development to correct the fundamental cause of Stargardt disease, according to Ascidian.
Ascidian hopes ACDN-01, which replaces 22 exons of the ABCA4 gene—which carry mutations that cause the inherited retinal disorder—can go beyond the capabilities of ADAR.
“ADAR is very good at making a specific change at a very specific location,” Robert Bell, chief scientific officer at Ascidian, told BioSpace. “With ACDN-01, we can correct hundreds [of mutations] across that patient population.”
ACDN-01 enables Ascidian to remove exons 1 through 22 in a patient’s pre-mRNA and replace it with wild type mRNA, Bell explained. “Any disease-causing mutation spanning that region we can correct with a single medicine.”
Another challenge is delivery, Rosan said. “There’s no question that across the genetic medicine space, delivery continues to be a barrier. How do you get your drug to the cells where it needs to go?”
On this note, Ascidian inked a deal with Roche in June 2024 worth up to $1.8 billion to discover RNA exon editing candidates for neurological diseases. “Ascidian’s strategy is very deliberately to focus on making the best RNA editors that we can and then partnering with collaborators like Roche to help us with the delivery challenge,” Rosan said.
“The field generally, and Roche specifically, have made tremendous strides in delivering therapeutics across the blood brain barrier—and, to other tissues of interest,” Rosan said.
With further progress could come additional challenges, Rouskin said. She noted that off-target effects are an important consideration for RNA editing, as they are for gene editors. However, “I think it’s much less important, and especially with such low editing efficiency, at this point. If you had 100% editing, I’m sure the off-targets will go up as well and then you can worry more about this, but I think the field is not there yet.”
While Rouskin said that current RNA editing capabilities are “still very limited.” Once it is possible to edit any base to another, “then you can go after, really, any disease that’s understood well enough to let you know what needs to be fixed.”
