the race begins with a successful first attempt

RNA editing has gained momentum in recent years as a potentially safer alternative to gene editing to treat genetic diseases. A human study was highly anticipated, and Massachusetts-based Wave Life Sciences took the reins and began one last year. Today, Wave is the first to carry out RNA editing in the clinic, taking a new step forward.

Recent results from 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 light activity, ability reduced to exercising 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 affects approximately one in 1,500 to 3,500 people of European ancestry, according to MedlinePlus.

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

The disease is caused by variants in the SERPINA1 gene, which lead to the aggregation of alpha-1-antitrypsin (AAT) in cells – a protein that protects the lungs from inflammation and damage. People with the ZZ genotype suffer from the most severe form of the disease and represent approximately 200,000 people living in the United States 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, requiring patients to undergo liver transplantation. RNA editing could offer patients a unique treatment.

“Performing the first ever therapeutic RNA editing in humans is an important milestone for our organization, for our GSK collaboration and for the entire oligonucleotide field. This also unlocks and de-risks 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 modification. LOVE,” said Paul Bolno, President and CEO of Wave. Life Sciences, in a press release.

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

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

Wave Life Sciences Phase 1 Trial Results Deemed Positive

Circulating wild-type M-AAT protein in plasma reached an average of 6.9 micromolars on day 15, representing more than 60% of total AAT. Increases in neutrophil elastase inhibition from baseline – an enzyme against which AAT protects the lungs – were consistent with the production of functional M-AAT. Mean total AAT protein increased from baseline to 10.8 micromolars on day 15, reaching the level that served as the basis for regulatory approval of AAT augmentation therapies. AAT levels increased from baseline from day 3 through day 57.

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

“This data also reinforces our confidence in our wholly-owned pipeline, including our programs in Huntington’s disease, Duchenne muscular dystrophy (DMD) and obesity, as well as our upcoming RNA editing targets. We look forward to showcasing upcoming 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 occurred. The phase 1b/2 trial is ongoing and patients have reported mild to moderate side effects. Once the trial is complete, GSK will drive the remainder of the candidate’s journey, as it has entered into 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 Wave’s share price to rise 63%, despite Japanese multinational Takeda’s announcement that it had abandoned its pact to develop a Huntington’s disease program, with Wave falling on the same day.

In space: preclinical studies of Korro and Ascidian in progress

Still, some analysts don’t see Wave leading the RNA editing charge. According to a report from Investor’s Business Daily, RBC Capital Markets analyst Luca Issi believes Massachusetts-based Korro Bio is poised to rule the space. Korro has long been battling Wave to bring its RNA-editing therapy AATD 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 natural ADAR editing system to repair the mutation causing AATD and restore normal AAT protein levels.

Unlike Wave’s approach, Korro’s is an IV drip, which is heavier, but Issi noted it might be more effective because it can result in higher protein levels.

Issi added: “While we recognize that WVE is ahead, we continue to believe that KRRO is the best place to play RNA publishing given unconstrained economics (compared to over 80% of revenue from WVE going to GSK) and what we support is better editing efficiency at lower doses.

As Korro advances KRRO-11 to the preclinical stage after reaching AAT levels in rodents within the first week, another Massachusetts-based biotech, Ascidian Therapeutics, hopes to shape the field. Ascidian’s trial is the first to test exon editing in patients, having received the green light from the US Food and Drug Administration (FDA). Sea squirt gets 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 pieces of RNA code called 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 matter builds up on the macula, leading to vision loss. More than 1,000 mutations in the ABCA4 gene cause Stargardt disease. However, loss of function of ABCA4 cannot be resolved 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 solution to correct the mutation.

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