CRISPR Shows Advantages Over Targeting PCSK9 to Treat High Cholesterol

A variation of CRISPR gene-editing technology may be a powerful way to elicit the protective effects of a genetic mutation that lowers cholesterol levels and associated risks of heart disease, according to a new study published by Circulation.
Individuals with mutations that cause the ANGPTL3 gene to stop functioning are known to have lower levels of blood triglycerides and low-density lipoprotein cholesterol, as well as a reduced risk of coronary heart disease. Currently, this mutation is not known to have any ill health effects, making ANGPTL3 an ideal target for novel drugs.
Previous studies have shown that single copies of the ANGPTL3 mutations occur in 1 out of every 250 individuals of European heritage, while individuals with 2 copies are even rarer.
In the new study, the authors aimed to determine whether a variation of CRISPR that does not require breaks in the DNA, called base-editing, could introduce ANGPTL3 mutations to lower cholesterol levels.
First, the researchers injected normal mice with base-editing therapy for the ANGPTL3 gene.
After 1 week, sequencing of liver samples showed a 35% editing rate with no off-target mutations, according to the study.
Additionally, mean levels of blood lipids were up to 30% lower among mice that underwent gene therapy compared with control animals.
In the second part of the study, the researchers compared plasma cholesterol and triglyceride levels for ANGPTL3 mice with those injected with a base-editing treatment for another liver gene, PCSK9.
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After 1 week, ANGPTL3 therapy resulted in a similar lowering of cholesterol but a much more significant decrease in triglycerides compared with PCSK9 therapy, according to the study.
Current PCSK9 inhibitors have been shown to reduce cholesterol and the risk of heart attack and stroke; however, the drugs have not been found to lower triglycerides, according to the study.
In the third stage of the study, the authors examined the viability of base-editing ANGPTL3 in mouse models of homozygous familial hypercholesterolemia. Targeting PCSK9 has not been very effective in this model, the authors noted.
After 2 weeks, treated mice had a 56% reduction in triglycerides and a 51% reduction in cholesterol compared with untreated mice, according to the study.
The authors are currently working to explore this treatment option in human liver cells transplanted into mice in order to determine safety and efficacy.
“This proof-of-principle study showed that base-editing of ANGPTL3 is a potential way to permanently treat patients with harmful blood lipid levels,” said lead researcher Kiran Musunuru, MD, PhD, MPH. “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 1-time CRISPR ‘vaccination’ might be ready to use in these patients within 5 years.”

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