Wave Life Sciences has reported the first-ever therapeutic RNA editing in humans, achieved in its RestorAATion-2 trial for alpha-1 antitrypsin deficiency (AATD).
In this phase 1b/2a trial, a single subcutaneous dose of WVE-006 resulted in significant restoration of wild-type M-AAT protein levels in two patients with the “ZZ” genotype of AATD, a genetic disorder linked to lung and liver disease. The edited protein accounted for more than 60% of total alpha-1 antitrypsin (AAT) levels, showing durability up to 57 days post-dose.
The study demonstrated that the plasma levels of total AAT reached approximately 11 micromolar, with mean wild-type M-AAT representing over 60% of the total AAT. These results suggest that RNA editing can restore levels consistent with the "MZ" genotype, which has a lower risk of developing AATD-related lung and liver disease. The trial is ongoing, and Wave Life Sciences plans to share data from a multidose cohort in 2025.
WVE-006 was well tolerated, with all adverse events classified as mild to moderate, and no serious adverse events reported.
Wave holds exclusive rights to develop and commercialize WVE-006, with GSK set to take over these responsibilities after the completion of the RestorAATion-2 study. Wave could receive up to $525 million in milestone payments and royalties on net sales under this agreement.