New Lipid Nanoparticles Deliver CRISPR-Cas9 to Knock Down Angptl3 in Mice

A team of researchers has developed a new way to deliver CRISPR-Cas9 genome editing tools directly to the liver, targeting a gene called Angptl3 that’s linked to high cholesterol and triglyceride levels. This breakthrough could pave the way for new treatments for lipoprotein metabolism disorders, which are a major risk factor for heart disease.

Why Target Angptl3?

Angptl3, or angiopoietin-like 3, is an enzyme that regulates levels of fats in the blood. Some people naturally have mutations in the Angptl3 gene that cause it to stop working, leading to lower levels of LDL cholesterol and triglycerides without any apparent health issues. Because of this, Angptl3 has become a hot target for new cholesterol-lowering therapies. Current treatments include monoclonal antibodies and antisense oligonucleotides (ASOs), which have shown promise in clinical trials, but these approaches are short-lived and need frequent doses.

The Promise of CRISPR-Cas9

CRISPR-Cas9 offers a more permanent solution by directly editing genes in the body. The Cas9 enzyme acts like molecular scissors, cutting DNA at precise locations guided by RNA molecules. Once the DNA is cut, the cell’s natural repair mechanisms kick in, often disabling the targeted gene. However, getting CRISPR components safely and efficiently into the right cells has been a major hurdle. Viral vectors have been used but come with risks like unintended genetic mutations and immune reactions.

Lipid Nanoparticles to the Rescue

Enter lipid nanoparticles (LNPs), tiny fat-like particles that can carry RNA and other molecules into cells. LNPs are already used in some FDA-approved drugs for delivering siRNA, a technology similar to CRISPR but less permanent. Researchers have now developed a new type of LNP that delivers Cas9 mRNA and a guide RNA targeting Angptl3, directly to liver cells in mice.

The new LNP, known as 306-O12B, was shown to be significantly more efficient than the FDA-approved MC-3 LNP, which is considered the gold standard for delivering nucleic acids to the liver. In tests with wild-type C57BL/6 mice, the LNP system knocked down the Angptl3 gene in the liver, leading to substantial reductions in serum levels of ANGPTL3 protein, LDL cholesterol, and triglycerides.

Long-Lasting Effects Without Side Effects

One of the standout findings of this study is the durability of the gene editing effects. A single dose of the LNP-CRISPR system maintained its therapeutic impact for at least 100 days, far longer than current antibody or ASO treatments. Importantly, no off-target effects were detected at the top nine predicted sites, and there were no signs of liver toxicity, making this approach both effective and safe in the tested mice.

What This Means for the Future

This study highlights the potential of using LNPs for delivering CRISPR-Cas9 in a safe and targeted way, specifically for treating disorders like hyperlipidemia that have a clear genetic component. By offering a more permanent fix compared to traditional therapies, this method could reduce the need for frequent treatments and improve patient outcomes.

While more research is needed, especially in larger animals and eventually humans, the success of this LNP system in mice is a promising step toward the clinical use of CRISPR-based therapies. If these findings hold up in further studies, we could be looking at a new frontier in the fight against heart disease and other conditions linked to high blood lipid levels.

This innovative approach not only makes genome editing safer and more precise but also underscores the growing role of nonviral delivery methods like LNPs in advancing gene therapy. As the technology continues to evolve, it brings us closer to the goal of making gene therapy accessible and affordable for everyone.

This discovery is yet another exciting chapter in the ongoing story of CRISPR, showing just how far we’ve come—and how much potential still lies ahead—in the quest to edit our way to better health.

PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.

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