biostudies-literatureUnknown54(2)Monian PWave Life SciencesAlpha-1 antitrypsin deficiency (AATD) is both a gain- and loss-of-function disease that impacts the liver and lung. 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. We have developed SERPINA1-994, an 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 M-AAT protein. SERPINA1-994 addresses loss of AAT functiNucleic acids researchgkaf1518https://www.ebi.ac.uk/biostudies/studies/S-EPMC12802959biostudies-literatureRNA editing for the treatment of alpha-1 antitrypsin deficiency.PMC12802959Rheinhardt JBowman KRossi JGiangrande PHChatterjee APurcell-Estabrook EStandley SShivalila CBriem SSingh KPatil SGodfrey JFaraone ALamattina APaik IHIwamoto NYang HMonian PDufresne JCannon MKandasamy PByrne MRanade ALu GPu TShimizu MThomas CDesai JFavaloro FBylsma MYu HHuth OMcGlynn ALemaitre MLindsey AGhosh AYin YNarayanan PHernandez NMetterville JYordanoff RTripathi SLuu KVargeese CDallaire MFriend SLooby RPan QKawamoto TLiu FfalseRNA 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. 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. We have developed SERPINA1-994, an 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 M-AAT protein. SERPINA1-994 addresses loss of AAT functi2026-01-01T00:00:00Z2026 Jan2026-06-11T03:12:19.226Z2026-06-11T03:08:15.945ZS-EPMC128029594153357710.1093/nar/gkaf1518