RNA editing in humans: the race begins with first successful trial

Photo credits: Cottonbro Studio
RNA editing

RNA editing has picked up steam in recent years as a potentially safer alternative to gene editing to treat genetic diseases. A study in humans was much anticipated, and Massachusetts-based Wave Life Sciences took the reins and began one last year. Now, Wave is the first to achieve RNA editing in the clinic, crossing yet another milestone.

The recent results of the GSK-partnered trial were based on data from two patients with alpha-1 antitrypsin deficiency (AATD), a genetic disorder characterized by symptoms such as shortness of breath after mild activity, reduced ability to exercise, and wheezing. It can also lead to emphysema, which is a lung disease caused by damage to the alveoli – the small air sacs in the lungs. Its prevalence varies by population and it affects about one in 1,500 to 3,500 people with European ancestry, according to MedlinePlus. 

How can RNA editing address limitations of current alpha-1 antitrypsin deficiency treatments?

The disease is caused by variants in the SERPINA1 gene, which leads to the aggregation of alpha-1-antitrypsin (AAT) in cells – a protein that protects the lungs from inflammation and damage. Those with the genotype ZZ have the most severe form of the disease, and account for around 200,000 people living in the U.S. and Europe.

Treatment options for AATD lung disease are currently limited to weekly intravenous (IV) therapy and there are no approved treatments for liver disease, leaving patients to undergo liver transplantation. RNA editing could offer patients a one-time treatment.

“Achieving the first-ever therapeutic RNA editing in humans is a significant milestone for our organization, for our GSK collaboration, and for the entire oligonucleotide field. It also unlocks and derisks Wave’s RNA editing platform, in light of the continued strong clinical translation of our proprietary best-in-class chemistry, including PN, stereochemistry and our N3U AIMer modification,” said Paul Bolno, president and chief executive officer at Wave Life Sciences, in a press release

The trial by Wave was a proof-of-mechanism study, where the two patients received a single 200 mg dose of WVE-006. The candidate is designed to correct the single base in the mutant SERPINA1 mRNA by reverting the mutant A (adenosine) to an I (inosine), which cells read as G. This approach aims to reduce AAT protein aggregation in the liver, restore circulating, functional wild-type AAT to protect the lungs from proteases, and retain physiological regulation of the AAT protein.

Since neither patient can naturally produce the AAT protein, the presence of the protein after treatment was the goal that was set for the trial. 

Wave Life Sciences’ phase 1 trial results deemed positive

Circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT. Increases in neutrophil elastase inhibition from baseline – an enzyme that AAT protects the lungs from – were consistent with production of functional M-AAT. The mean total AAT protein increased from baseline to 10.8 micromolar at day 15, meeting the level that has been the basis for regulatory approval for AAT augmentation therapies. AAT levels rose from baseline as early as day three and through day 57.

“The level of mRNA editing we are observing with a single dose exceeded our expectations and we expect M-AAT levels to continue to increase with repeat dosing, based on our preclinical data. These initial data, alongside WVE-006’s durability and convenient subcutaneous administration, are all supportive of a best-in-class profile for WVE-006 relative to other editors and in the broader AATD space,” said Bolno. 

“These data also increase our confidence in our wholly-owned pipeline, including our Huntington’s disease, Duchenne muscular dystrophy (DMD), and obesity programs, as well as our next RNA editing targets. We look forward to introducing the next RNA editing programs, as well as providing an update on our INHBE GalNAc-siRNA program in obesity, at our Research Day on October 30.”

The therapy was found to be well-tolerated and has shown a favorable safety profile so far. No serious adverse events took place. The phase 1b/2 trial is ongoing and patients have reported mild to moderate side effects. Once the trial ends, GSK will pilot the rest of the candidate’s journey, since it struck a $170 million deal with Wave in 2022 for global licensing rights. Wave is eligible for up to $525 million in milestones.

These results led to Wave’s share price going up by 63% despite news of Japanese multinational Takeda blowing off its pact to develop a Huntington’s disease program with Wave falling on the same day.

In the space: Korro and Ascidian’s preclinical studies ongoing

Yet some analysts don’t see Wave leading the RNA editing charge. According to a report by Investor’s Business Daily, RBC Capital Markets analyst Luca Issi thinks Massachusetts-based Korro Bio is poised to run the space. Korro has long been racing against Wave to bring its AATD RNA editing therapy to the clinic. Its preclinical candidate KRRO-110 is an RNA editing oligonucleotide that is delivered to liver cells using a lipid nanoparticle (LNP) delivery system. Once inside these cells, KRRO-110 uses the naturally occurring ADAR editing system to repair the mutation that causes AATD and restore normal levels of AAT protein. 

Unlike Wave’s approach, Korro’s is an IV infusion, which is more cumbersome, but Issi noted that it could be more effective as it can result in higher protein levels. 

Issi added: “While we acknowledge WVE is ahead, we continue to believe that KRRO is the better way to play RNA editing given unconstrained economics (vs 80%+ of WVE revenue going to GSK) and what we argue is a better editing efficiency at lower doses.” 

While Korro is making moves with KRRO-11 in the preclinical stage having achieved AAT levels in rodents as early as week 1, another Massachusetts-based biotech, Ascidian Therapeutics, hopes to shape the field. Ascidian’s trial is the first to test exon editing in patients, after it was given the go-ahead from the U.S. Food and Drug Administration (FDA). Ascidian gets both its name and technology from sea squirts, which are ocean creatures and primordial ancestors of vertebrates. To grow from larvae to adults, ascidians shuffle small bits of RNA code known as exons. Inspired by this mechanism, Ascidian uses a synthetic RNA molecule to intervene in the splicing process and persuade the cell to swap out a bunch of problematic exons for a corrected copy. 

Its candidate ACDN-01 targets the genetic cause of Stargardt disease – a rare genetic eye disease that occurs when fatty material builds up on the macula, causing vision loss. More than 1,000 mutations across the ABCA4 gene have been found to cause Stargardt disease. However, loss of function of ABCA4 cannot be addressed by standard gene replacement, given the large size of the gene, or by base editing, due to the high mutational variance of the affected gene. This is why RNA editing could be the answer to correcting the mutation.

Although opinions vary on who will head the RNA editing field now that it has been tested in humans, Wave’s 2025 multidose results and upcoming clinical proof-of-concept data from Korro  might help put this debate to rest.

Explore other topics: genetic disordersRNA technology

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