A variation of CRISPR gene editing could potentially be used to mimic the protective effects of a genetic mutation linked to lower cholesterol levels and heart disease risks.

The success of the technique was discovered by researchers from the Perelman School of Medicine at the University of Pennsylvania when they applied it to a mouse model. The research team, led by associate professor of cardiovascular medicine Kiran Musunuru, MD, PhD, MPH, used the mouse model to assess whether base editing – a variation of CRISPR genome editing that does not require breaks in the double-strand of DNA – could be used in humans to introduce mutations into the gene for ANGPTL3 to reduce blood lipid levels.

Patients with naturally occurring mutations that cause a loss of function in the gene for ANGPTL3 have reduced blood triglycerides, LDL cholesterol, and risk of coronary heart disease, with no apparent detrimental consequences to their health. This makes the ANGPTL3 protein a key target for new heart disease drugs. Earlier studies at the Perelman School of Medicine found that single copies of inactivating mutations in ANGPTL3 are found in about one in every 250 people of European heritage. However, people with mutations in both copies of the gene are rarer.

Musunuru said: “This proof-of-principle study showed that base-editing of ANGPTL3 is a potential way to permanently treat patients with harmful blood lipid levels. It would be especially useful in patients with a rare condition called homozygous familial hypercholesterolemia, which causes sky-high cholesterol levels and dramatically increased risk of heart attack. They are very difficult to treat with today’s medications, and a one-time CRISPR ‘vaccination’ might be ready to use in these patients within five years.”

The study was done in three parts. First, the team injected normal mice with the base-editing treatment for the ANGPTL3 gene. A week later, sequencing of the ANGPTL3 target site in liver samples from the mice revealed a median 35% editing rate in the target gene and no off-target mutations. The mean levels of blood lipids were significantly lower in the treated mice, by up to 30% compared to untreated mice.

Next the researchers compared mice with the modified ANGPTL3 gene to those injected with a base-editing treatment for another liver gene, PCSK9, for plasma cholesterol and triglycerides. After a week, ANGPTL3 targeting caused a similar reduction in cholesterol but a much greater decline in triglycerides compared to targeting PCSK9. The PCSK9 protein is the target of currently available medications which has been shown to reduce cholesterol as well as the risk of heart attack and stroke.

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Lastly, the team looked at how base editing of the ANGPTL3 gene performed in a mouse model of homozygous familial hypercholesterolemia as removing PCSK9 had little effect. After two weeks, the treated mice showed 56% reduced triglycerides and a 51% decrease in cholesterol levels compared to untreated mice.

Musunuru’s research team is now preparing to test CRISPR-based treatments against the human ANGPTL3 gene in human liver cells transplanted into mice. They hope this will provide the important information on efficacy and safety that will be needed before human trials can begin.