Cytosine base editing of LPA in transgenic mice averts large deletions

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

doi:10.1016/j.ymthe.2026.02.049

Cytosine base editing of LPA in transgenic mice averts large deletions

Mol Ther. 2026 Mar 3:S1525-0016(26)00178-4. doi: 10.1016/j.ymthe.2026.02.049. Online ahead of print.

Authors

Marcel A Chuecos¹, So Hyun Park², Madhvi M Bhakta³, Usosa Too-Chiobi³, Daniel Betancourth², Mingming Cao², Marco De Giorgi³, Christopher J Walkey³, Anjana Tiwari⁴, Biana Godin⁵, Julia M Assini⁶, Donna J Palmer⁷, Philip Ng⁷, Michael B Boffa⁶, Marlys L Koschinsky⁸, Gang Bao², William R Lagor⁹

Affiliations

¹ Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Bioengineering, Rice University, Houston, TX 77030, USA.
³ Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Center for BioNanoEngineering, Houston Methodist Research Institute, Houston, TX 77030, USA.
⁵ Center for BioNanoEngineering, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA.
⁶ Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5B7, Canada; Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5B7, Canada.
⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5B7, Canada; Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5B7, Canada.
⁹ Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: lagor@bcm.edu.

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: AAV; CRISPR; LPA; adenovirus; base editing; cholesterol; genome editing; heart disease; lipoprotein(a).

Abstract

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