Hereditary primary hemochromatosis is one of the most common inborn errors of metabolism in Europe. In this disease, also known as iron storage disease, the body has too much iron. Excess iron builds up in organs and tissues and causes slowly progressive damage to the liver, heart, pancreas, pituitary gland, and joints. This can lead to changes in the heart muscle (cardiomyopathy) or diabetes (bronchial diabetes), and even scarring of liver tissue (cirrhosis) and liver cancer.
The reason is that a genetic defect disrupts the regulation of iron absorption through the mucosa of the small intestine. A research team led by Prof. Michael Ott and Dr. Simon Krooss from the Department of Gastroenterology, Hepatology and Endocrinology at the Hannover Medical School (MHH) has now found a way to treat inherited diseases with the help of targeted gene correction. The work has been published in Nature Communications journal. Poorly controlled iron absorption
“In most cases, iron storage diseases are due to hemochromatosis A defect in the disease gene HFE, which is located on chromosome 6,” Professor Otter said. It only occurs in people who have inherited the defect from both parents, i.e. people who have no “healthy” genes to compensate. A specific change called the C282Y mutation is found in both copies of the HFE gene in more than 80 percent of those affected. This results in the replacement of amino acids (ie, protein building blocks) in the HFE protein.
As a result, the HFE protein loses its ability to control iron absorption into enterocytes. In order to empty the iron stores and normalize the iron concentration in the body, the patient must undergo a life-long phlebotomy. “It’s stressful, and it doesn’t work for everyone,” the hepatologist noted. Drugs that directly bind iron in the body and thus neutralize it are also not ideal because of its strong side effects.
Cells initiate repair
Therefore, MHH researchers are Seek a different approach. They use the body’s own repair mechanisms to repair the defective HFE gene. With the help of CRISPR/Cas technology known as “genetic scissors” and accompanying biotech tools, they specifically altered a tiny defective building block in the mutated HFE gene.
In technical terms, this process is called base editing. What’s special about this kind of gene repair is that the genetic scissors are used in a way that does not simply cut the DNA double-strand exactly at the desired location, as in classical applications. “Double-strand breaks always carry some risk of harmful mutations,” say doctors and scientists. On the other hand, with base editing, the two single strands are separated from each other and only one strand is changed.
” So the cell automatically initiates its natural repair process and adds the correct nucleotides to the second strand , so that the C282Y mutation disappears throughout the duplex,” explains Dr. Krooss.
Mouse model: blood iron Content significantly decreased
Research Team This biotech trick was studied in a mouse model. With a single injection, the gene correction rate was 12%. “This is a huge success because most genetic diseases can already be controlled if 5 percent of cells have the right genes,” said Dr. Alice Rovai, lead author of the study. Four months after the intervention, iron levels in the blood had dropped significantly. In addition, the researchers expected further reductions in iron levels after twelve months. “The repair system is sluggish, so it takes time for more liver cells to undergo gene correction.”
But the research team wanted to do more many. So far, they have packaged the CRISPR/Cas system with molecular tools in so-called viral vectors, also known as gene taxis, and administered them by injection into mice. In a next step, the researchers hope to try sending only the mRNA blueprint of the base editing system — similar to an mRNA vaccine against the SARS-CoV-2 coronavirus.
“This is safer and more efficient because we can get rid of the viral vector and maybe increase the success rate to 30 to 40 %,” Dr Cross said. If this is successful and the application also works in humans, a single injection could save people with severe hemochromatosis in the future from liver cancer and organ removal.
“Injection replaces transplant,” said liver researcher Ott. In addition, base editing may be a therapeutic option for many congenital diseases where a single defective gene is the cause.
More information:
Alice Rovai et al, In vivo adenine base editing restores C282Y and improves iron metabolism in hemochromatosis mice, Nature Communications (2022). DOI: 10.1038/s41467-022-32906-9
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