Cytosine Base Editing of Lpa in Transgenic Mice Averts Large Deletions

Authors

• Marcel A Chuecos
• So Hyun Park
• Madhvi M Bhakta
• Usosa Too-Chiobi
• Daniel Betancourth
• Mingming Cao
• Marco De Giorgi
• Christopher J Walkey
• Anjana Tiwari
• Biana Godin
• Julia M Assini
• Donna J Palmer
• Philip Ng
• Michael B Boffa
• Marlys L Koschinsky
• Gang Bao
• William R Lagor

Language

English

Publication Date

6-3-2026

Journal

Molecular Therapy

DOI

10.1016/j.ymthe.2026.02.049

PMID

41782368

PMCID

PMC13015817

PubMedCentral® Posted Date

3-26-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease, with approximately 20% of the population exhibiting elevated levels. While there are promising drugs in development, there are currently no approved therapies specifically designed to lower Lp(a) levels. For high-risk individuals with extreme levels of Lp(a), liver-directed genome editing could be an effective one-time solution. Genome editing approaches such as CRISPR and TALENs can reduce Lp(a) in LPA-transgenic mouse models, but they frequently induce large and potentially harmful genomic deletions. Here, we report the first application of TadA-derived cytosine base editing (CBE), delivered via helper-dependent adenovirus (HDAdV) and adeno-associated virus (AAV) vectors, to introduce premature stop codons into LPA. This strategy produced robust and durable lowering of circulating apolipoprotein(a) (apo(a)) in LPA-transgenic mice. Using SMRT-seq with single-molecule unique molecular identifiers, we quantified deletion events and found that CBE did not induce large deletions when targeting a single LPA site and produced only a small fraction (< 4%) of large deletions when editing across multiple sites. In contrast, CRISPR-Cas9 cutting of LPA resulted primarily in large deletions. These findings demonstrate that CBE enables sustained reduction of circulating apolipoprotein(a) in an LPA-transgenic mouse model while largely preserving genomic integrity.

Keywords

Animals, Mice, Transgenic, Mice, Gene Editing, Lipoprotein(a), Genetic Vectors, Dependovirus, Cytosine, Adenoviridae, Humans, Sequence Deletion, CRISPR-Cas Systems, LPA, Lipoprotein(a), AAV, Adenovirus, CRISPR, Base Editing, Genome Editing, Cholesterol, Heart Disease

Published Open-Access

yes

Recommended Citation

Chuecos, Marcel A; Park, So Hyun; Bhakta, Madhvi M; et al., "Cytosine Base Editing of Lpa in Transgenic Mice Averts Large Deletions" (2026). Faculty, Staff and Students Publications. 7153.
https://digitalcommons.library.tmc.edu/baylor_docs/7153