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Published on: September 27, 2013
In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease
Jennifer Khirallah1, Hanan Bloomer1,2, Douglas Wich1
1Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA.
Insights
Gene therapy using CRISPR adenine base editors (ABEs) offers a potential one-time treatment for cardiovascular disease (CVD). This approach successfully lowered blood lipid levels, including low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs), in mice for over 100 days.
Area of Science:
- Biotechnology
- Cardiovascular Medicine
- Genetics
Background:
- Cardiovascular disease (CVD) is a leading global cause of death, often linked to high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs).
- Current treatments require daily medication, leading to poor patient adherence and limited long-term efficacy.
- Gene therapy presents a promising alternative for durable lipid reduction, with ANGPTL3 identified as a key target due to its role in lipid metabolism and cardioprotective loss-of-function variants.
Purpose of the Study:
- To develop and evaluate a novel gene therapy strategy for reducing blood lipid levels.
- To investigate the efficacy of CRISPR adenine base editors (ABEs) delivered via lipid nanoparticles for targeting the ANGPTL3 gene.
- To assess the durability of lipid-lowering effects and the potential for a one-and-done treatment for CVD.
Main Methods:
- CRISPR adenine base editors (ABEs) were packaged into lipid nanoparticles with guide RNA targeting a critical splice site in the Angptl3 gene.
- The ABE-containing lipid nanoparticles were administered intravenously to mice.
- Base editing efficiency in the liver, serum ANGPTL3 levels, and blood lipid profiles (LDL-C, TGs) were monitored over time.
Main Results:
- Achieved over 60% base editing efficiency in the liver, leading to sustained reduction of serum ANGPTL3 levels.
- Demonstrated durable reductions in serum LDL-C and TGs for at least 100 days post-treatment.
- Maintained low blood lipid levels even when mice were subjected to a high-fat, high-cholesterol diet up to 191 days after therapy.
Conclusions:
- CRISPR ABE-mediated gene disruption of ANGPTL3 is an effective strategy for durable reduction of blood lipids.
- This gene therapy approach shows potential as a one-and-done treatment for managing hyperlipidemia and reducing CVD risk.
- The findings provide a strong foundation for developing novel, long-lasting therapies for cardiovascular disease.
Abstract:
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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