Cytosine base editing of LPA in transgenic mice averts large deletions
- Mol Ther. 2026 Jun 3;34(6):3334-3352. doi: 10.1016/j.ymthe.2026.02.049.
- 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: [email protected].
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.