26 October 2022

Injection will save you from excess iron

Hereditary primary hemochromatosis is one of the most common congenital metabolic disorders in Europe. In this disease, also known as iron accumulation disease, the body is overloaded with iron. Its excess accumulates in organs and tissues and leads to slowly progressive damage to the liver, heart, pancreas, pituitary gland and joints; cardiomyopathy, diabetes mellitus, cirrhosis and even liver cancer occurs.

The cause of hemochromatosis is a genetic defect that disrupts the regulation of iron absorption through the mucous membrane of the small intestine. A research team led by Professor Dr. Michael Ott and Dr. Simon Krooss from the Department of Gastroenterology, Hepatology and Endocrinology at the Hanover Medical School has found a way to treat hereditary hemochromatosis using genes.

In most cases, iron accumulation disease occurs due to a defect in the HFE gene, which is located on chromosome 6. This occurs only in people who inherited this defect from both parents, that is, who do not have a "healthy" variant of the gene to compensate. In more than 80% of patients, a change called the C282Y mutation was detected in both copies of the HFE gene. This leads to the replacement of one amino acid in the HFE protein.

As a result, HFE loses its ability to control iron absorption in intestinal cells. In order to empty iron reserves and normalize the concentration of iron in the body, patients have to agree to lifelong phlebotomy – bloodletting in order to remove blood iron from the body. This procedure often scares patients and is not always effective. Medications that bind iron directly in the body and thus neutralize it are also not ideal because of the strong side effects.

Therefore, the researchers decided to use the body's own resources to restore the defective HFE protein. Using CRISPR/Cas technology and an accompanying biotechnological tool, they modified a defective block in the mutated HFE gene.

The peculiarity of gene repair in this study was that the gene scissors did not completely cut the double strand of DNA in the desired area, as in the classical version. Two separate chains were separated from each other, and only one of them was edited.

In this case, the cell automatically launches a natural recovery program and includes the correct nucleotide also in the second chain, so that the C282Y mutation disappears in the entire double chain.

The research team tested this biotechnological trick on a mouse model. With a single injection, the rate of gene correction was 12%. This is considered a success because most genetic diseases can already be controlled if 5% of cells have the correct gene.

The level of iron in the blood of mice decreased significantly four months after the intervention. In addition, the researchers expect to see a further decrease in iron levels after twelve months – the recovery system is slow, so more liver cells need time to correct the gene.

But the work does not stop there. The CRISPR/Cas system with a molecular instrument was packaged into a viral vector and injected. At the next stage, the researchers plan to introduce only an mRNA scheme for the editing system – similar to vaccines with mRNA against the SARS-CoV-2 coronavirus. This is safer and more effective, because the absence of a viral vector will increase the probability of success by up to 30-40%. If successful, one such injection can save people seriously suffering from hemochromatosis and its complications, and avoid liver cancer and organ removal.

Article by A.Rovai et al. In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice published in the journal Nature Communications.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru .

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