A compact base editor rescues AATD-associated liver and lung disease in mouse models

Jenny Gao; Nathan Bamidele; Debora Pires-Ferreira; Chunwei Zheng; April Destefano; Haoyang Cheng; Qiushi Tang; Yueying Cao; Jun Xie; Guangping Gao; Alisha Gruntman; Erik Sontheimer; Terence R Flotte; Wen Xue

doi:10.1016/j.ymthe.2025.08.040

A compact base editor rescues AATD-associated liver and lung disease in mouse models

Mol Ther. 2025 Nov 5;33(11):5817-5828. doi: 10.1016/j.ymthe.2025.08.040. Epub 2025 Aug 28.

Authors

Affiliations

¹ RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
² Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
³ Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
⁴ Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01605, USA.
⁵ RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: erik.sontheimer@umassmed.edu.
⁶ Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: terry.flotte@umassmed.edu.
⁷ RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: wen.xue@umassmed.edu.

PMID: 40883986
PMCID: PMC12448179 (available on 2026-08-28)
DOI: 10.1016/j.ymthe.2025.08.040

Abstract

Alpha-1 antitrypsin deficiency (AATD) is commonly caused by a G-to-A mutation in the SERPINA1 gene (the PiZ mutation). The mutant PiZ AAT protein is sequestered in hepatocytes, causing lung emphysema due to insufficient AAT protein to inhibit neutrophil elastase in the lung. Here, we show that a compact adenine base editor (ABE) with an evolved Cas9 nickase derived from Neisseria meningitidis (eNme2.C) can be packaged in a single AAV and correct the PiZ mutation in mouse models of AATD. An all-in-one eNme2.C-TadA8e/guide 2 plasmid achieved approximately 20% on-target editing in PiZ reporter cells. TadA9e demonstrated sequence-specific reduction in bystander editing compared to TadA8e, without significantly affecting the on-target edit. In PiZ transgenic mice, eNme2.C-TadA9e AAV showed approximately 23% editing efficiency after 8 weeks and reduced liver disease burden in treated mice. In a new AAT-null;PiZ transgenic mouse model, ABE restored serum levels of AAT to beyond the 570 μg/mL therapeutic level. Moreover, ABE treatment was able to significantly correct lung functions in AAT-null;PiZ animals with emphysema. This study demonstrates the feasibility of an eNme2.C-based ABE in a single AAV to treat both AATD-associated liver and lung disease.

Keywords: AAV; base editing; gene editing; mouse liver; rare diseases.

MeSH terms

Animals
CRISPR-Cas Systems
Dependovirus / genetics
Disease Models, Animal
Gene Editing* / methods
Genetic Therapy* / methods
Genetic Vectors / genetics
Humans
Liver Diseases* / etiology
Liver Diseases* / genetics
Liver Diseases* / therapy
Lung Diseases* / etiology
Lung Diseases* / genetics
Lung Diseases* / therapy
Mice
Mice, Transgenic
Mutation
alpha 1-Antitrypsin Deficiency* / complications
alpha 1-Antitrypsin Deficiency* / genetics
alpha 1-Antitrypsin Deficiency* / therapy
alpha 1-Antitrypsin* / genetics

Substances

alpha 1-Antitrypsin

Abstract

MeSH terms

Substances

Grants and funding