CRISPR against atherosclerosis: details
Gene therapy against heart attack
Maxim Rousseau, Polit.roo
Doctors from the USA have announced plans to introduce a gene therapy method aimed at significantly reducing the risk of a heart attack (Harvard University, Broad Institute extend CRISPR human therapeutics license to Verve Therapeutics). To do this, it will be enough for a person to make just one injection.
So far, the authors expect to begin clinical trials of their method in the next three years on patients with a rare genetic disease that makes them prone to heart attacks at the age of 30-40 years. If the method turns out to be safe and effective for them, doctors will request permission to use it for other patients with a high risk of heart attack. "We believe that therapy will be relevant for any adult who is at risk of a heart attack," says Sekar Kathiresan, a cardiologist and geneticist from Harvard Medical School, head of the research team. "We want it to be intended not only for people who are at risk of a heart attack at a young age due to a genetic disease, but also for a large number of patients at risk of heart attack."
Now in many countries, cardiovascular diseases have become the most common cause of death. Approximately 18 million people die from them a year, in 85% of cases death occurs due to a heart attack or stroke. Patients who are at risk of a heart attack should take a range of medications, such as blood thinners, cholesterol-lowering statins and remedies for high blood pressure. Most of them should be taken daily for the rest of their lives, but many people eventually stop taking medications.
The authors of the new technique hope to radically change the approach to coronary heart disease and move from a model of chronic care to a single injection. The method is being developed at the Center for Genomic Medicine of Massachusetts General Hospital (Massachusetts General Hospital) by a specially created startup Verve Therapeutics, which received $ 58.5 million from investors.
The new method will not directly affect the heart, but the liver cells that are involved in the production of low-density lipoproteins (those that carry the so-called "bad cholesterol" in the blood, which increases the risk of atherosclerosis and its consequences such as coronary artery disease, heart attack and stroke). Cholesterol is necessary for the body for a number of tasks, for example, it participates in the construction of cell membranes and the synthesis of vitamin D. Since cholesterol is not soluble in water, it cannot be transported through the blood in its pure form. To transfer cholesterol molecules bind to special transport proteins, forming lipoproteins. The PCSK9 protein produced in liver cells prevents the removal of low-density lipoproteins from the body. To date, several medications aimed at this protein and lowering cholesterol levels in the blood are already being used.
Recent studies have shown that some people have mutations that significantly reduce the production of low-density lipoproteins in the body and, accordingly, reduce the risk of atherosclerosis and heart failure. For example, approximately 0.02% of African Americans have only one working copy of the PCSK9 gene instead of the usual two copies. "These people are healthy and surprisingly resistant to heart attacks," says Sekar Kathiresan.
The PCSK9 gene will be the target of a new therapy method. With the help of the Crispr-Cas9 genome editing tool, doctors hope to turn off this gene in liver cells. If it stops working in 30% – 40% of cells, the risk of a heart attack will decrease significantly. To deliver the genetic construct and the Cas9 protein, lipid nanospheres are used, designed in such a way that they accumulate in the liver. For the patient, the treatment will consist of one intravenous injection. Recently, we talked about a similar study in which Secar Kathiresan also participated, where cholesterol reduction was provided by a mutation in another gene – ANGPTL3.
Kiran Musunru, a geneticist from the University of Pennsylvania and chief scientific consultant at Verve Therapeutics, used genome editing to modify the PCSK9 gene in mice and achieved a 35-40% reduction in cholesterol levels. If subsequent trials on monkeys are also effective, scientists will try to move on to treating humans.
The first evidence of such success already exists, however, in these experiments a different method of genome editing and delivery of a therapeutic construct to liver cells was used. In July last year, James Wilson and his colleagues from the University of Pennsylvania reported on the results of an experiment on rhesus monkeys, in which an artificially constructed meganuclease molecule was used for genome editing, and a modified adenoassociated virus was used as a delivery vehicle. Four months later, up to 64% of the liver cells in six monkeys participating in the experiment carried the disabled PCSK9 gene. With the maximum number of such cells, the content of PCSK9 protein in the blood of monkeys fell by 84%, and the cholesterol level associated with low–density lipoproteins - by 60%.
First of all, Sekar Kathiresan and his colleagues will try to help patients with homozygous familial hypercholesterolemia using a new method. People with this genetic disease have very high cholesterol levels, and it is less susceptible to correction by conventional means, such as diet or taking statins. In some cases, they require a higher dose of cholesterol-lowering drugs, and sometimes, with homozygous hypercholesterolemia, when a pathological mutation is contained in both copies of the gene, they even have to resort to regular apheresis of low-density lipoproteins (a procedure resembling dialysis) or even a liver transplant is required. The most common problem with familial hypercholesterolemia is the development of coronary heart disease at a much younger age than usual. This leads to angina or heart attack. The arteries of the brain are less often affected, which leads to brief bouts of weakness on one side of the body or inability to speak, and in some cases a severe stroke occurs.
Scientists expect that clinical trials of their method will begin in three years. Of course, the new therapy is accompanied by all the same traditional concerns that are associated with any attempt to edit the genome for medical purposes. The main one is the uncertainty that only the target gene will be affected. If the patient can simply stop taking pills with serious side effects, then gene therapy is almost irreversible. "The problem with any gene therapy is that you can't stop treating patients," says Sian Harding, professor of cardiological pharmacology at Imperial College London. – We need cholesterol for some things, and if you reduce it too much, it will have devastating consequences for the body. This is a problem if it is not controllable and irreversible."
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