Gene therapy of atherosclerosis
Disabling the gene in the liver of monkeys lowered the level of cholesterol in their blood
For the first time, scientists managed to edit genes in most of the liver of experimental monkeys, as a result of achieving a decrease in cholesterol in their blood. Perhaps this method can be used in the treatment of heart diseases. The authors also believe that in the future they will be able to correct the consequences of dangerous mutations.
Quite a lot of studies have already been conducted in which the genome is edited for therapeutic purposes. But usually they are carried out ex vivo, that is, the patient's cells are extracted from the body, in laboratory conditions their DNA is edited using the CRISPR/Cas9 method or some other, and then they are returned to the patient. Experiments on genome editing at the embryonic stage have also been carried out. Much less common are in vivo experiments, when the genome is edited directly in a living organism.
This time, the researchers' goal was the PCSK9 gene, which encodes a protein that prevents the removal of cholesterol from the blood. 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 insoluble in water, it cannot be transported through the blood in its pure form. To transfer cholesterol molecules bind to special transport proteins, forming lipoproteins. However, there are so-called low-density lipoproteins, and it is with them that "bad cholesterol" is associated, which increases the risk of atherosclerosis and its consequences such as heart attacks and strokes. The PCSK9 protein produced in the liver prevents the removal of these lipoproteins. There are several medications aimed at this protein and lowering cholesterol levels in the blood.
Gene therapy specialist James Wilson and his colleagues from the University of Pennsylvania decided to fight not with the PCSK9 protein, but with the gene responsible for this protein. To succeed, they needed to turn off this gene in a sufficiently large number of liver cells. Conducting an experiment on rhesus monkeys, they used an artificially constructed meganuclease molecule for genome editing, and a modified adenoassociated virus as a delivery vehicle.
After four months, 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%.
The results of the study are published in the journal Nature Biotechnology (Wang et al., Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol).
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