Evidence map›Paper›PMID 40883986›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2025

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 and 4 more

Abstract read
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In one paragraph

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Jenny GaoRNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Nathan BamideleRNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Debora Pires-FerreiraHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Chunwei ZhengRNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
April DestefanoHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Haoyang ChengRNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Qiushi TangHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Yueying CaoRNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Jun XieHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Guangping GaoLi 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.
Alisha GruntmanHorae 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.
Erik SontheimerRNA 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.
Terence R FlotteLi 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.
Wen XueRNA 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.

Funding

Vector Immunology CoreP01HL158506 · NHLBI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Wen Xue · 2021 to 2026
$19.5M
Develop combinatorial non-viral and viral CRISPR delivery for lung diseasesUH3HL147367 · NHLBI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ANDERSON, DANIEL G, GAO, GUANGPING · 2021 to 2022
$2.9M
In vivo prime editing for precision cancer mouse modelsR01CA275945 · NCI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Wen Xue · 2023 to 2026
$2.5M
Advanced Delivery Platforms for Base Editing In VivoR01GM150273 · NIGMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ERIK J. SONTHEIMER, Wen Xue · 2023 to 2026
$2.4M
Developing a novel adenine base editor tool for in vivo alpha-1 antitrypsin deficiency gene correction.F30HL176024 · NHLBI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Jenny Gao · 2024 to 2026
$103k
NCI NIH HHS R01 CA275945NHLBI NIH HHS F30 HL176024NHLBI NIH HHS P01 HL158506NHLBI NIH HHS UH3 HL147367NIGMS NIH HHS R01 GM150273
6 · The paper itself

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.

Indexed as

alpha 1-Antitrypsinalpha 1-Antitrypsin DeficiencyGene EditingGenetic TherapyLiver DiseasesLung DiseasesAnimalsCRISPR-Cas SystemsDependovirusDisease Models, AnimalGenetic VectorsHumansMiceMice, TransgenicMutationalpha 1-AntitrypsinAAVbase editinggene editingmouse liverrare diseases

Identifiers

PMID40883986
PMCPMC12448179

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.