A The CRISPR form is expected to be more secure and possibly more effective than the original has passed its first substantive test. When the CRISPR “base edition” was used to remove two genes associated with cholesterol in monkeys, the animals’ blood levels of LDL (“bad”) cholesterol and triglycerides causing heart disease were reduced as much as 60% and 65% , respectively, Sekar Kathiresan, co-founder and CEO of Verve Therapeutics, announced Saturday at the (virtual) meeting of the International Society for Stem Cell Research.
The results, from Verve’s experiments on 14 cynomolgus monkeys (also known as crab-eating macaques), are the first published data showing the successful editing of the CRISPR base in a non-human primate; There have been similar successes in mice. So it’s good news not just for Verve, which was founded last year to develop CRISPR-based cures for cardiovascular disease, but also for Beam Therapeutics, a two-year-old company.
developing CRISPR-based editors for a long list of diseases. Verve licensed Beam’s “Adenine Base Editor” for her experiment.
“Our goal is to develop a single genome editing drug for heart disease,” Kathiresan told STAT before her ISSCR talk.
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The grassroots editors pointed to one of the two genes that both monkeys and humans have: PCSK9 and ANGPTL3. In 2006, scientists discovered that a broken copy of PCSK9, a gene that produces an enzyme involved in cholesterol metabolism, causes a 28% reduction in an individual’s average LDL cholesterol (compared to people with two working copies. of the gene) and an 88% reduction in the lifetime risk of coronary heart disease. About 1 in 50 people have at least one disabled PCSK9. When ANGPTL3 is disabled, scientists discovered in 2010 that triglycerides are also at low levels, and the lifetime risk of heart attack is reduced by 34%. About 1 in 300 people have a mutation that turns off at least one of their copies of ANGPTL3.
Both genes are expressed in the liver, which is why the Verve scientists sent their base editor (locked in a lipid nanoparticle). “The idea is to confer, with a basic edition, the protection that some rare people naturally have,” said Kathiresan.
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In the seven macaques that received the PCSK9-directed CRISPR base editor by intravenous infusion, blood levels of the PCSK9 protein dropped 89%, indicating high editing efficiency. After two weeks, the monkeys’ LDL cholesterol levels had dropped 59%.
In the seven who received the base editor ANGPTL3, blood levels of the ANGPTL3 protein fell 95%. “Basically we were able to turn off this gene,” said Kathiresan. Blood levels of triglycerides in these monkeys fell 64% and LDL cholesterol 19%.
The scientists did not examine the liver cells of the animals to see if the base editor hit regions of the genome that were not supposed. But the Verve scientists observed no serious adverse events in the macaques, and when the base editor was used in human hepatocytes growing in laboratory dishes, there was no evidence of such an off-target issue.
That security profile supports one of the key advantages of CRISPR base editors over classic CRISPR. Both forms of genome editing use an RNA guide to bring the CRISPR molecule to the intended site in the genome (Kathiresan credits a large RNA guide, chosen from hundreds, for the high levels of gene editing they obtained in macaques). But classic CRISPR then cuts the double helix, which can cause random insertions, reversals, and general chaos in the target DNA.
The core editors, instead, focus on their goal and then, without cutting the double helix, change a single letter of DNA. That dramatically reduces the risk of genomic chaos.
Beam licensed its base editors PCSK9 and ANGPTL3 to Verve because “we think they were in a much better position to develop this,” said Beam CEO John Evans, given the cardiovascular expertise of Kathiresan and its co-founders. “Otherwise, these goals would have been on our list, but I’m not sure when we would have reached them. Licensing makes a lot of sense to us. ”
Joseph Wu of Stanford University, an expert in genomic therapy for cardiovascular disease who is not involved with Verve, said the degree of LDL and triglyceride decrease in macaques “looks good compared to statins.” But because Verve showed only a couple of weeks of data, he said, “I’d like to know what the long-term effect is.”
An equally important question is whether the world needs genome editing for high cholesterol, atherosclerosis, and cardiovascular disease, given the low cost and ease of use of statins.
In many people with familial hypercholesterolemia, which affects 1 in 200 to 500 people, “treatment with statins alone is not enough to lower LDL,” Wu said, making this rare population a reasonable target for genome therapy. . Unlike PCSK9 targeting drugs Repatha (from Amgen) and Praluent (Sanofi and Regeneron), which are given by injection every two to four weeks, CRISPR could be a unique cure, Beam’s Evans said: “You wouldn’t have to treat women people forever, so payers go back. ” PCSK9 medications are priced at about $ 450 per month.
“Genome editing is potentially permanent and therefore a unique therapy, assuming it is safe and effective,” Wu agreed. “Therefore, the lifetime cost may possibly be less than [the PCSK9 drugs]. It’s also more convenient because patients don’t need to go to the clinic every month or two. “
However, Verve has dreams beyond those with familial hypercholesterolemia. “We really want to transform the way we think about cardiovascular disease,” said Kathiresan. Instead of taking statins for decades or, more precisely, prescribing statins, since half of the people who were prescribed cholesterol-lowering medications after a heart attack stopped taking them within a year, people who Undergoing gene therapy, if all goes well, they will have the same protection against heart disease as individuals with natural mutations in PCSK9, ANGPTL3, or six other protective genes in Verve’s view.
The company expects this year to select which of its potential gene therapies to prioritize, with the goal of launching a clinical trial by 2023. “We are pretty confident,” said Kathiresan.
