RNA Editing With WVE-006 Restores Functional AAT, Cuts Z-AAT in AATD

WVE-006, an investigational RNA editing oligonucleotide, increased functional wild-type M-AAT and reduced mutant Z-AAT in adults with Pi*ZZ alpha-1 antitrypsin deficiency (AATD), according to interim results from the phase 1/2a RestorAATion-2 trial presented at AASLD The Liver Meeting 2026.¹ Investigators described the findings as first-in-human proof of mechanism for therapeutic RNA editing.¹

Pavel Strnad, MD, of University Hospital RWTH Aachen, presented the data and discussed them in an interview with HCPLive. He explained AATD originates in the liver but affects the whole body, making genetic correction in hepatocytes the most direct approach. Because RNA is a short-lived message, he said, editing it offers a safety advantage over permanently altering DNA.

“In this class of drugs, it’s really the first time it worked, and it’s actually incredible how smooth it went,” Strnad said.

How Does WVE-006 Correct the AATD Mutation?

WVE-006 is a GalNAc-conjugated oligonucleotide designed to edit hepatocyte SERPINA1 mRNA, converting Z-AAT to functional M-AAT.¹ Strnad explained the approach relies on an endogenous deaminase enzyme to alter a single base, correcting the individual mutation rather than silencing the entire gene. Unlike augmentation therapy, which raises plasma AAT without addressing hepatic Z-AAT production, the approach could address both lung and liver disease.¹

RestorAATion-2 (NCT06405633) is evaluating single and multiple ascending subcutaneous doses of WVE-006 at 200, 400, and 600 mg (n = 8 per cohort) in Pi*ZZ participants.¹ After a single dose and 12 weeks of follow-up, participants received biweekly (200 mg) or monthly (400 and 600 mg) dosing for 12 weeks, followed by 12 weeks of observation. Serum M-AAT, Z-AAT, and total AAT were measured by liquid chromatography-mass spectrometry.¹

Single doses of 200, 400, and 600 mg produced M-AAT levels representing 44%, 48%, and 52% of total AAT, with Z-AAT reductions of 47%, 50%, and 59%, respectively.¹ In the 200 mg and 400 mg multiple-dose cohorts, M-AAT reached 64% and 59% of total serum AAT, with Z-AAT reductions of 71% and 68%.¹

What Questions Remain for RNA Editing in AATD?

WVE-006 was generally well tolerated, with all adverse events mild to moderate and no serious adverse events.¹ Investigators also observed increases in total endogenous AAT during acute phase responses. After a single 200 mg dose, total AAT rose above 20 µM during 1 such response, and 2 acute phase responses in the 400 mg multiple-dose cohort raised total AAT by 58% and 60%.¹

HCPLive previously reported the first clinical demonstration of RNA editing in humans from the initial 200 mg cohort of RestorAATion-2 in 2024, when a single dose raised mean total AAT to approximately 11 µM.² Strnad cautioned the data remain limited to a small number of patients, and editing does not yet correct all mutant transcripts.

“We are not able to repair 100% of the variant. Only maybe 50%,” he said.

Recent multisociety consensus guidance on AATD-associated liver disease, which Strnad coauthored, noted preservation of pulmonary function is not necessary for inclusion in trials of therapies increasing AAT through DNA or RNA editing.³ The investigators concluded the approach paves the way for targeted correction of single-nucleotide mutations.¹

References:

1. Strnad P, Turner A, Conron M, et al. RNA editing for the treatment of alpha-1 antitrypsin deficiency (AATD): interim results from RestorAATion-2. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.

2. First-ever human RNA editing achieved in RestorAATion-2 trial of WVE-006 for AATD. HCPLive. Published October 16, 2024. Accessed November 9, 2026. https://www.hcplive.com/view/first-ever-human-rna-editing-achieved-restoraation-2-trial-wve-006-aatd

3. Loomba R, Clark VC, Mandorfer M, et al. Multi-society expert panel consensus guidance regarding clinical assessment and clinical trial endpoints in adults with alpha-1 antitrypsin deficiency-associated liver disease. Gastroenterology. 2026;170(4):829-842. doi:10.1053/j.gastro.2025.12.012