B101-10 RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD)
K R Chapman, A M Turner, P Strnad, M Conron, W Griffiths, P Hernandez, J R Hurst, H Yla Outinen, V Goel, J Haegele, K Longo, M McLaughlin, P Monian, M Monine, P Narayanan, S Patel, A Siddiqui, A Strahs, C Shivalila, L Xie, C I Wright, C F CaractaAbstract
Rationale
Severe AATD is commonly caused by homozygous mutations in the SERPINA1 gene (Pi*ZZ), resulting in misfolded Z-AAT protein in the liver and offering decreased protection for the lung against neutrophil elastase. Current standard of care focuses on augmenting serum AAT levels through weekly infusions of human plasma-purified AAT to maintain serum levels above a putative protective threshold (11 µM). Liver disease is not addressed by this intervention. WVE-006, an investigational N-Acetylgalactosamine-conjugated RNA editing oligonucleotide, is designed to recruit endogenous ADAR enzymes to edit SERPINA1 mRNA in hepatocytes, replacing Z-AAT with M-AAT synthesis. This approach aims to increase serum M-AAT levels while reducing Z-AAT, preserve endogenous regulation of AAT expression, and address both lung and liver manifestations of severe AATD.
Methods
RestorAATion-2 (NCT06405633) is an ongoing phase 1b/2a clinical trial evaluating the safety, tolerability, pharmacodynamics, and pharmacokinetics of single- and multiple-ascending doses of WVE-006 (200, 400, 600 mg; n = 8 per cohort) in individuals with a ZZ genotype. Participants received a single subcutaneous dose of WVE-006 with a 12-week observation period, followed by biweekly (200 mg) or monthly doses (400, 600 mg) for 12 weeks, with a subsequent 12-week observation period. Serum levels of M-AAT, Z-AAT and total (M + Z) AAT were measured by LC-MS/MS assays, while functional AAT levels were assessed by a neutrophil elastase inhibition assay.
Results
In the 200 mg multidose cohort, mean maximum serum M-AAT levels reached 7.2 μM in ZZ individuals, corresponding to 64.4% of total serum AAT (11.9 μM). Increases in functional AAT activity were consistent with M-AAT production and were accompanied by 60.3% decrease in Z-AAT protein. In the 200 and 400 mg single dose cohorts, M-AAT levels increased to 4.8 μM and 5.3 μM, respectively. During the 200 mg single dose phase, one participant experienced an acute-phase response due to a kidney stone, during which total serum AAT levels reached 20.6 μM. WVE-006 has been generally safe and well tolerated; all adverse events have been mild to moderate, with no serious adverse events.
Conclusions
These data, which show production of M-AAT, lowering of Z-AAT protein, and endogenous upregulation of AAT protein in individuals with a ZZ genotype during stress provide proof-of-concept for the first RNA editing therapy to enter clinical testing.
This abstract is funded by: Wave Life Sciences