RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is both a gain- and loss-of-function disease that impacts the liver and lung.1 Most severe cases result from a homozygous missense mutation in the SERPINA1 gene (Z mutation). While current therapies and those in development may ameliorate lung or liver disease, few are designed to address both.1 We have developed SERPINA1-994, a N-Acetylgalactosamine-conjugated chemically modified oligonucleotide that elicits adenine-to-inosine RNA editing using endogenous adenosine deaminases acting on RNA enzymes, to correct SERPINA1 Z transcripts. We show that SERPINA1-994 edits 50% of the Z transcript in hepatocytes of NSG-PiZ mice, which increases total serum AAT levels and induces the production of wild-type protein. SERPINA1-994 addresses loss of AAT function in lung by increasing the neutrophil elastase inhibition capacity of mouse serum and gain-of-function in liver by decreasing protein aggregation, decreasing inflammation and correcting gene expression patterns. SERPINA1-994 relies on a clinically proven delivery technology and directs highly specific RNA rather than DNA editing, so there is no risk for permanent off-target effects. Overall, these data suggest that SERPINA1-994 changes a ZZ homozygous state, which is associated with a high risk for AATD, to a low-risk MZ-like phenotype. Overall design: NSG-PiZ mice, a model for AATD that expresses the human SERPINA1 Z transgene, were treated with AIMERs to restore WT SERPINA1. Mutant mice were treated with AIMER to correct mutation and the resulting transcriptome was examined to observe both AIMER editing as well the restoration of a healthier mouse transcriptome after AIMER editing