Researchers have developed a CRISPR base editor delivered via lipid nanoparticles to inactivate the ANGPTL3 gene in the liver, potentially offering a single-dose treatment for high cholesterol and triglycerides.
The treatment consists of guide RNA and mRNA encoding an adenine base editor packaged in a GalNAc-lipid nanoparticle. In human liver cells, the base editor modified the target ANGPTL3 gene with no detectable off-target edits across approximately 3,000 candidate sites and no treatment-related structural variants.
In nonhuman primates, a single dose produced a greater than 90 percent mean reduction in circulating ANGPTL3 protein. Effects persisted for at least 3 years. In mouse and nonhuman primate models of high cholesterol and triglycerides, the gene inactivation reduced LDL cholesterol by approximately 40 to 50 percent and triglycerides by 50 to 70 percent. The treatment was well-tolerated in primates.
The research, published in Nature, has led to an ongoing first-in-human clinical trial in patients with refractory hyperlipidemia syndromes. High LDL cholesterol and triglyceride-rich lipoproteins are leading risk factors for atherosclerotic cardiovascular disease, and most patients do not achieve target lipid levels with existing medications.