Molecular therapy : the journal of the American Society of Gene TherapyAug 30, 2025

A small gene editor may improve liver and lung disease linked to AATD in mice

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A single-AAV compact adenine base editor corrected PiZ SERPINA1 and improved AATD liver and lung disease readouts in mice.

Evidence

Preclinical base-editing study in PiZ reporter cells, PiZ transgenic mice, and AAT-null;PiZ mice reported about 20% reporter-cell editing, about 23% in vivo editing after 8 weeks, serum AAT above 570 ug/mL, and improved lung function.

Caveat

The rescue is shown in cells and mouse models, with the main in vivo editing result reported after 8 weeks rather than long-term or human outcomes.

Simplified

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.

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A small gene editor may improve liver and lung disease linked to AATD in mice

Abstract

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