In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease

Jennifer Khirallah; Hanan Bloomer; Douglas Wich; Changfeng Huang; J. Noah Workman; Yamin Li; Gregory A. Newby; David R. Liu; Qiaobing Xu

Molecular Therapy: Nucleic Acids (Jun 2025)

In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease

Jennifer Khirallah,
Hanan Bloomer,
Douglas Wich,
Changfeng Huang,
J. Noah Workman,
Yamin Li,
Gregory A. Newby,
David R. Liu,
Qiaobing Xu

Affiliations

Jennifer Khirallah: Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
Hanan Bloomer: 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
Douglas Wich: Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
Changfeng Huang: Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
J. Noah Workman: Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Yamin Li: Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
Gregory A. Newby: Department 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.
David R. Liu: 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.
Qiaobing Xu: 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.

Journal volume & issue: Vol. 36, no. 2
p. 102486

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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