And form the CRISPR widely expected to be safer and perhaps more efficient that the original passed its first major test. When CRISPR “editing basics” was used to knock out two cholesterol-associated genes in monkeys in the animal blood levels of heart-disease-causing LDL (“bad”) cholesterol and triglycerides fell as much as 60% and 65%, respectively, Shekhar Kathiresan, co-founder and CEO of Verve therapies, announced Saturday at the (virtual) meeting of the International Society for stem cell research.
The results obtained from the experiments of Verve in 14 macaque (and.to.and. crab-eating macaques), the first published data according to successful CRISPR base editing in non-human primates; there has been a similar success in mice. They are therefore good news not only for inspiration, which was based last year for the development of CRISPR-based treatment of cardiovascular diseases, radiation therapy, and two-year-old company
development Editors CRISPR database for a long list of diseases. Take away the license of “basic editor beams adenine” for my experiment.
“Our goal is to develop a one-and-done editing of the genome, the cure for heart disease,” said Kathiresan stat ahead of his ISSCR to speak.
Database editors targeted one of the two genes, which are like monkeys and people: PCSK9 and ANGPTL3. In 2006, scientists discovered that one broken copy of the PCSK9, the gene that produces the enzyme involved in the metabolism of cholesterol, leading to 28% reduction of the individual means LDL (compared with people with two working copies of the gene) and 88% reduction in lifetime risk of coronary heart disease. About 1 in 50 people have at least one PCSK9 from people with disabilities. When ANGPTL3 disabled scientists discovered in 2010, the triglycerides also in the rock-bottom level and life expectancy the risk of heart attack is reduced by 34%. About 1 300 people with a mutation that disables at least one of their copies of ANGPTL3.
How genes are expressed in the liver, therefore, scientists are encouraged to sent them based editor (encapsulated in lipid nanoparticles). “The idea is to confer with editing the database, the protection that some rare people, of course,” said Kathiresan.
Seven monkeys who received the PCSK9 settings editor CRISPR database using the infusion, the blood levels of the protein PCSK9 fell by 89%, indicating high efficiency of editing. After two weeks, the monkeys, the levels of LDL cholesterol fell by 59%.
In seven, received a basic editor ANGPTL3, blood levels of ANGPTL3 protein fell by 95%. “We were actually able to turn off this gene,” said Kathiresan. The levels of these monkeys triglycerides in the blood fell by 64% and LDL by 19%.
Scientists have studied the cells of animals liver, to see if the editor hit regions of the genome should not. But scientists enthusiasm were no serious adverse events in monkeys, and when the base editor has been used on human hepatocytes growing in a Petri dish, there was no evidence of such past editing.
What the safety profile supports one of the key advantages of the CRISPR system database editors for classic CRISPR. Both forms of editing of the genome to use guide RNAS to carry the CRISPR molecules to the intended site on the genome (Kathiresan loans great guide RNA selected from hundreds for high level editing of the genes that they received in macaques). But then classic CRISPR shortens the double helix, which can lead to accidental insertions, inversions, and General chaos in the target DNA.
Basic Editors, in contrast, home to its target and then, without cutting the double helix, change one letter of DNA. Which greatly reduces the risk of genomic chaos.
Ray licensed its PCSK9 and ANGPTL3 base editors with enthusiasm, because “we thought they were in a much better position than US to develop it,” – said General Director of Tufts John Evans, given the vascular examination Kathiresan and its co-founders. “Otherwise, these tasks were on our list, but I’m not sure when we would get them. Licensing made a lot of sense for us.”
Joseph Wu of Stanford University, an expert on genome therapy of cardiovascular diseases, which are not connected with enthusiasm, said the LDL and triglycerides, decrease in macaques “looks good on the background of statins”.But as enthusiasm was shown only a few weeks of data, he said, “I would be curious to know what long-term effect.”
Not less important question-does the world Need editing of the genome for high cholesterol, atherosclerosis, and cardiovascular disease, statins, given the low cost and ease of use.
Many people with familial hypercholesterolemia, which affects 1 in 200 to 500 people, “the statin-alone treatment is not sufficient to lower LDL levels,” Wu said, making this rare population is a reasonable goal in gene therapy. In contrast to PCSK9 have drugs Repatha (from Amgen) and Praluent (Sanofi and Regeneron), which are given by injection every two to four weeks, the CRISPR can be one-Time treats, said Beam Evans: “You don’t have to treat people forever, so the payers to push back.” On PCSK9 drugs at at a price of about $ 450 per month.
“Editing the genome potentially permanent and therefore, a one-time therapy, suggesting that it safely and effectively,” agreed Woo. “Thus, the cost of living may be lower than [the PCSK9 drugs]. It is even more convenient because patients don’t need to go to the clinic every month or two.”
Verve has dreams for people with familial hypercholesterolemia, however. “We really want to change how we think about cardiovascular disease,” said Kathiresan. Instead of taking statins for decades — or, more precisely, the prescribed statins, as half of the people prescribed for cholesterol-lowering drugs after a heart attack stop taking them within a year — people who undergo gene therapy if all goes well, there is the same protection against heart disease as people with natural mutations at the PCSK9, ANGPTL3, or protective genes six other spectacular sights.
The company expects this year to choose which of its potential gene therapy primarily for the purpose of conducting clinical trials by 2023. “We are quite confident,” said Kathiresan.
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