Gene therapy against strong drinks
Mice were taught to stop in time when the degree of alcohol increases
Polina Loseva, N+1
American scientists have worked on mice a new way to combat alcohol addiction – to block the enzyme aldehyde dehydrogenase selectively in the liver. This method avoids a lot of side effects from standard alcoholism therapy. In addition, it leaves the body tolerant to small doses of alcohol. In humans, such a method could allow people to drink wine or beer, but would prohibit patients from drinking stronger drinks. The study is published in the journal Proceedings of the National Academy of Sciences (Guillot et al., Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking).
Two enzymes are responsible for removing alcohol from the blood in the human body. The first – alcohol dehydrogenase – turns it into acetic aldehyde, and the second – aldehyde dehydrogenase-2 (ADH) – finally breaks it down to acetic acid. If the aldehyde is not destroyed in time, it accumulates in tissues, including in the brain and liver, and causes many unpleasant effects, such as nausea, pain and cardiac arrhythmias. This happens not only with alcohol abuse, but also as a result of congenital mutations in the ADH-2 gene, which occur in about 8 percent of people.
Modern drugs that are used to treat alcohol addiction mimic the condition of people who carry the mutation. They block the work of ADG-2 and cause unpleasant sensations when a person drinks alcohol. At the same time, ADG-2 has another function inside the cells: it neutralizes toxic aldehydes that are formed during oxidative stress. Therefore, blocker drugs have a lot of side effects, and doctors are looking for new ways to interfere with the work of ADH.
A group of scientists from the National Institutes of Health in Bethesda, led by Bin Gao, proposed selectively turning off ADH in different tissues. To test as much as possible, they created a series of knockout mice: with ADH genes turned off in the liver, spleen, intestines, adipose tissue or throughout the body.
These animals were given alcohol to drink and after a while the concentration of aldehyde in the blood was measured. It turned out that in those mice whose ADH did not work only in the liver, aldehyde accumulated four times less than in those who were deprived of it completely, but twice as much as in those who had it turned off in other tissues. This suggests that the liver plays the most significant role in the neutralization of aldehyde, but other organs are also involved in this process.
The researchers then compared the body's response to alcohol in mice lacking the ADH gene completely or only in liver cells. They found out that in both cases, after drinking alcohol, the work of genes that are associated with an inflammatory response is triggered in the liver. However, in those animals in which the gene was turned off only in the liver, there were traces of organ damage – for example, the enzyme alanine aminotransferase (ALT) – there was less in the blood.
Scientists have suggested that mice with partially-turned-off ADH will, like mice with completely turned-off ADH, refuse large doses of alcohol, but may remain tolerant to small doses. To test this, they conducted a test with two bottles: mice were offered a choice between regular drinking water and gradually increasing concentrations of alcohol.
Ordinary mice preferred alcohol, starting with a strength of 3 degrees, then drank it more and more, and after 9 degrees gradually reduced the dose, and the 21-degree drink eventually amounted to only a quarter of the entire liquid consumed. Mice with missing ADH stopped drinking after 3 degrees and then did not choose alcohol regardless of the strength. But animals with partially turned off ADH – only in the liver – calmly tolerated weak drinks, and only after 9 degrees began to refuse stronger alcohol.
Then the authors of the work tried to selectively turn off ADH in the liver in ordinary mice. To do this, they injected an adenoviral vector with a small interfering RNA into their body. The vector, according to scientists, was supposed to selectively deliver RNA to liver cells, and it should have already contacted the RNA of the ADH protein and started its destruction. Such animals stopped drinking alcohol after 6 degrees of strength. The therapy also worked when it was administered later – to mice who were already accustomed to alcohol of a certain strength – under the influence of the viral vector, they began to lower the degree.
Based on their work, the researchers proposed a new way to combat alcohol addiction. Partial blockade of ADH gives the body enough trouble so that it does not seek to absorb alcohol of high strength, but in small doses – comparable to the strength of beer or wine – alcohol remains safe. Methods of turning off ADH in humans still, of course, have to be worked out. However, a similar drug has already been approved in the USA recently – it also acts on the basis of RNA interference and gets selectively into the liver - and this means that such therapy is theoretically possible.
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