In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease
Cardiovascular disease (CVD) is the leading cause of death globally and is exacerbated by elevated blood levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs). Existing approaches for decreasing blood lipid levels rely on daily medications, leading to poor patient adherence....
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| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225312500040X |
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| author | Jennifer Khirallah Hanan Bloomer Douglas Wich Changfeng Huang J. Noah Workman Yamin Li Gregory A. Newby David R. Liu Qiaobing Xu |
| author_facet | Jennifer Khirallah Hanan Bloomer Douglas Wich Changfeng Huang J. Noah Workman Yamin Li Gregory A. Newby David R. Liu Qiaobing Xu |
| author_sort | Jennifer Khirallah |
| collection | DOAJ |
| description | Cardiovascular disease (CVD) is the leading cause of death globally and is exacerbated by elevated blood levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs). Existing approaches for decreasing blood lipid levels rely on daily medications, leading to poor patient adherence. Gene therapy represents a promising ''one and done'' strategy to durably reduce blood lipid levels. ANGPTL3 has emerged as a potential target for gene therapy, as naturally occurring loss-of-function variants are cardioprotective. Here, we use lipid nanoparticles to package and deliver CRISPR adenine base editors (ABEs), which enable gene knockout without requiring potentially harmful DNA double-strand breaks. We package ABE mRNA and a synthetic guide RNA targeted to disrupt an important splice site in Angptl3, which we administered to mice intravenously. We achieved over 60% base editing in the liver and durable reductions in serum ANGPTL3, LDL-C, and TGs for at least 100 days. Notably, blood lipid levels remained low when mice were challenged with a high-fat high-cholesterol diet up to 191 days after therapy. These results provide a foundation for a potential one-and-done treatment for CVD. |
| format | Article |
| id | doaj-art-8ab596a629af4976a80add59a561dbf6 |
| institution | OA Journals |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-8ab596a629af4976a80add59a561dbf62025-08-20T02:04:33ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-06-0136210248610.1016/j.omtn.2025.102486In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular diseaseJennifer Khirallah0Hanan Bloomer1Douglas Wich2Changfeng Huang3J. Noah Workman4Yamin Li5Gregory A. Newby6David R. Liu7Qiaobing Xu8Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USADepartment of Biomedical Engineering, Tufts University, Medford, MA 02155, USA; School of Medicine and Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USADepartment of Biomedical Engineering, Tufts University, Medford, MA 02155, USADepartment of Biomedical Engineering, Tufts University, Medford, MA 02155, USADepartment of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USADepartment of Biomedical Engineering, Tufts University, Medford, MA 02155, USADepartment of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA; Corresponding author: Gregory A. Newby, Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA; Corresponding author: David R. Liu, Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA; School of Medicine and Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA; Corresponding author: Qiaobing Xu, Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA.Cardiovascular disease (CVD) is the leading cause of death globally and is exacerbated by elevated blood levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs). Existing approaches for decreasing blood lipid levels rely on daily medications, leading to poor patient adherence. Gene therapy represents a promising ''one and done'' strategy to durably reduce blood lipid levels. ANGPTL3 has emerged as a potential target for gene therapy, as naturally occurring loss-of-function variants are cardioprotective. Here, we use lipid nanoparticles to package and deliver CRISPR adenine base editors (ABEs), which enable gene knockout without requiring potentially harmful DNA double-strand breaks. We package ABE mRNA and a synthetic guide RNA targeted to disrupt an important splice site in Angptl3, which we administered to mice intravenously. We achieved over 60% base editing in the liver and durable reductions in serum ANGPTL3, LDL-C, and TGs for at least 100 days. Notably, blood lipid levels remained low when mice were challenged with a high-fat high-cholesterol diet up to 191 days after therapy. These results provide a foundation for a potential one-and-done treatment for CVD.http://www.sciencedirect.com/science/article/pii/S216225312500040XMT: RNA/DNA EditingCRISPR-Cas9base editinggene editingangiopoietin-like protein-3cardiovascular disease |
| spellingShingle | Jennifer Khirallah Hanan Bloomer Douglas Wich Changfeng Huang J. Noah Workman Yamin Li Gregory A. Newby David R. Liu Qiaobing Xu In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease Molecular Therapy: Nucleic Acids MT: RNA/DNA Editing CRISPR-Cas9 base editing gene editing angiopoietin-like protein-3 cardiovascular disease |
| title | In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease |
| title_full | In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease |
| title_fullStr | In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease |
| title_full_unstemmed | In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease |
| title_short | In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease |
| title_sort | in vivo base editing of angptl3 via lipid nanoparticles to treat cardiovascular disease |
| topic | MT: RNA/DNA Editing CRISPR-Cas9 base editing gene editing angiopoietin-like protein-3 cardiovascular disease |
| url | http://www.sciencedirect.com/science/article/pii/S216225312500040X |
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