Gene correction as a potential treatment for iron storage disease

MHH: Gene correction as a potential treatment for iron storage disease

(From left): Prof. Dr. Michael Ott, Dr. Simon Cross, and first author Dr. Alice Ruffy. Credit: Karen Kaiser/MHH.

Hereditary primary hemochromatosis is one of the most common inborn errors of metabolism in Europe. In this disorder, also known as iron storage disease, the body is overburdened with iron. Excess iron accumulates in organs and tissues and leads to gradual, gradual 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 genetic defect who disrupts regulation iron Absorption by the mucous membrane of the small intestine. A research team led by Prof. Dr. Michael Ott and Dr. Simon Cross from the Department of Gastroenterology, Hepatology and Endocrinology at the Medical School Hannover (MHH) has now found a way to treat the genetic disease with the help of targeted people. Gene Correction. The work was published in the magazine Nature Communications.

Defective iron absorption control

“In most cases, iron storage disease is caused by a defect in the hemochromatosis gene HFE, which is located on chromosome 6,” says Professor Ott. It occurs only in people who have inherited this defect from both parents, that is, who do not have a “healthy” gene to compensate. In more than 80% of those affected, a specific change, called the C282Y mutation, is found in both copies of the HFE gene. This leads to the replacement of one of the amino acids – the building block of protein – in the HFE protein.

As a result, HFE protein loses its ability to control iron absorption in intestinal cells. In order to unload iron stores and normalize the concentration of iron in the body, patients must accept phlebotomy for life. “This is stressful, and moreover, it doesn’t work for everyone,” notes the hepatologist. Medicines that bind iron directly in the body and thus neutralize it are also not ideal due to strong side effects.

The cell begins the repair program

So MHH researchers take a different approach. They use the body’s own repair mechanisms to repair the faulty HFE gene. With the help of CRISPR/Cas technology, known as “gene scissors,” and its accompanying biotechnology tool, they specifically altered a small defective building block in the mutated HFE gene.

In technical terms, the procedure is called basic editing. The special feature of this gene repair: gene scissors were used in a way that simply did not cut the double strand of DNA exactly at the desired position as in the classic application. “Double tuft fracture always carries a certain risk of unwanted mutations,” says the doctor and scientist. With basic editing, on the other hand, the two individual threads are separated from each other and only one of them is changed.

“As a result, the cell automatically starts its own natural repair program and includes the correct nucleotides in the second strand as well, so that the C282Y mutation in the double strand disappears completely,” Dr. Cross explains.

Mouse model: serum iron levels are significantly reduced

The research team investigated this biotechnological trick in a mouse model. With a single injection the rate of genetic correction was 12%. “This is a great success, because most genetic diseases can indeed be controlled if 5% of cells have the right gene,” says Dr. Alice Ruffay, first author of the study. Serum iron levels were already significantly reduced four months after the intervention. In addition, the researchers expect to see a further decrease in iron levels after twelve months. “The repair system is slow, so it takes more time for the liver cells to correct the genes.”

But the research team wants more. So far, they’ve packed the CRISPR/Cas system with the molecular tool of a so-called virus vector — also known as a gene taxi — and given it an injection into mice. In the next step, the researchers want to try to send only the mRNA blueprint for the basic editing system – similar to the mRNA vaccines against SARS-CoV-2.

“This is much safer and more effective because we can dispense with the viral vector, and possibly increase the success rate to 30-40%,” Dr. Cross says. If this works and the application also works in humans, a single injection in the future could save people with severe hemochromatosis due to liver cancer and organ removal.

“Injections instead of transplants,” says liver researcher Ott. In addition, basic modification can be a treatment option for many congenital diseases that are caused by a single defective gene.

Researchers report that the new approach doubles the efficiency of stem cell editing

more information:
Alice Rovai et al, in vivo adenine base deregulation leads to C282Y reversion and improved iron metabolism in hemochromatosis-deficient mice, Nature Communications (2022). DOI: 10.1038 / s41467-022-32906-9

Presented by Hannover Medical School

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