Key result
LNP-delivered CRISPR base editing achieves ~65% hepatic Angptl3 knockdown, durably lowering LDL-C and triglycerides.
Why the study?
Existing approaches to decrease blood lipid levels require daily medications leading to poor adherence, motivating exploration of gene therapy as a durable alternative.
Does in vivo base editing of Angptl3 via lipid nanoparticles safely reduce low-density lipoprotein cholesterol and triglycerides in mouse models?
Does in vivo base editing of Angptl3 via lipid nanoparticles safely reduce low-density lipoprotein cholesterol and triglycerides in mouse models?
In vivo adenine base editing of the Angptl3 gene via lipid nanoparticles safely provides durable, long-term reductions in LDL-C and triglycerides in mice, offering proof-of-concept for a 'one-and-done' genetic therapy for cardiovascular disease.
Answers are grounded in this paper and cite their sources.
Preclinical Angptl3 base editing durably lowers lipids in mice; leaves open translation to human cardiovascular therapy.
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.
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Khirallah et al. (2025) studied Cardiovascular disease (preclinical model). Adenine base editors targeting Angptl3 via lipid nanoparticles vs. Untreated controls was evaluated on Base editing in the liver and reduction in serum ANGPTL3, LDL-C, and TGs. Lipid nanoparticle delivery of CRISPR adenine base editors achieved 64.6% on-target editing of Angptl3 in mouse liver, durably reducing serum LDL-C and triglycerides.
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