March 1, 2024

Gene editing precisely repairs immune cells


The mutated T cells are unable to kill the B (red) cells induced by the Epstein-Barr virus. This causes other immune cells to flow to the area of ​​infection, thereby blocking a blood vessel (center).

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Credit: Elijah D. Lowenstein and Xun Li, K. Rajewsky Lab, Max Delbrück Center

Some inherited genetic defects cause an exaggerated immune response that can be fatal. Using the CRISPR-Cas9 gene editing tool, such defects can be corrected, thus normalizing the immune response, as researchers led by Klaus Rajewsky from the Max Delbrück Center now report in “Scientific Immunology.”

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare immune system disorder that usually occurs in infants and young children under the age of 18 months. The condition is serious and has a high mortality rate. It is caused by several genetic mutations that prevent the normal functioning of cytotoxic T cells. These are a group of immune cells that kill cells infected by viruses or otherwise altered cells. If a child with FHL contracts a virus – such as the Epstein-Barr virus (EBV), but also other viruses – the cytotoxic T cells cannot eliminate the infected cells. Instead, the immune response goes out of control. This leads to a cytokine storm and an excessive inflammatory reaction that affects the entire body.

“Doctors treat FHL with a combination of chemotherapy, immunosuppression and bone marrow transplantation, but many children still die from the disease,” says Professor Klaus Rajewsky, who heads the Laboratory for Immune and Cancer Regulation at the Max Delbrück Center. He and his team therefore developed a new therapeutic strategy. Using the gene-editing tool CRISPR-Cas9, researchers were able to repair defective T cells from mice and two seriously ill babies. The repaired cytotoxic T cells functioned normally, with the mice recovering from hemophagocytic lymphohistiocytosis. Rajewsky and his team have now published their findings in the journal “Scientific Immunology.”

Gene repair strategy works in mice

The starting point for the study were mice in which the team was able to mimic EBV infections. In these animals, researchers altered a gene called perforin so that its function was completely lost or severely compromised – a common genetic defect in patients with LFS. When they then provoked a condition similar to an EBV infection, the affected B cells multiplied uncontrollably because the defective cytotoxic T cells were unable to eliminate them. As a result, the immune response was accelerated and the mice developed hemophagocytic lymphohistiocytosis.

Next, the team collected memory T stem cells – that is, long-lived T cells from which active cytotoxic T cells can mature – from the mice’s blood. The researchers used the gene-editing tool CRISPR-Cas9 to repair the faulty perforin gene in memory T cells and then injected the corrected cells back into mice. The animals’ immune response calmed down and the symptoms disappeared.

How long the protection lasts is uncertain

The paper’s first author, Dr. Xun Li, used blood samples from two sick children to test whether the strategy also works in humans. One had a defective perforin gene, the other a different defective gene. “Our gene repair technique is more accurate than previous methods, and the T cells remain virtually unchanged after undergoing gene editing,” says Li. “It was also fascinating to see how effectively memory T cells could be multiplied and repaired. even from a small amount of blood.” Cell culture experiments showed that the babies’ repaired memory T cells were capable of a normal cytotoxic T cell response.

This means that the therapeutic mechanism works in principle. But before patients can benefit from this discovery, the team first needs to resolve open questions and test the treatment concept in clinical trials. “It is not yet known how long the protective effect lasts,” says Dr. Christine Kocks, a scientist on Rajewsky’s team. “Because memory T stem cells remain in the body for a long time, we hope the therapy will provide long-term or even permanent protection. It is also conceivable that patients could be treated with their repaired T cells repeatedly.”

The procedure is minimally invasive, as only a small amount of blood is needed and the mice did not require any preparatory treatment – ​​unlike, for example, a bone marrow transplant. “We sincerely hope that our mechanism of action will be a breakthrough in the treatment of FHL,” says Rajewsky, “either to buy more time for a successful bone marrow transplant or even as a treatment in itself.”

Max Delbrück Center

The Max Delbrück Center for Molecular Medicine of the Helmholtz Association (Max Delbrück Center) is one of the world’s leading biomedical research institutions. Max Delbrück, born in Berlin, was a Nobel laureate and one of the founders of molecular biology. At sites in Berlin-Buch and Mitte, researchers from around 70 countries study human biology – investigating the foundations of life, from its most elementary building blocks to system-wide mechanisms. By understanding what regulates or disrupts the dynamic balance of a cell, an organ or the entire body, we can prevent diseases, diagnose them earlier and stop their progression with personalized therapies. Patients must be able to benefit as quickly as possible from the discoveries of basic research. That’s why the Max Delbrück Center supports the creation of spin-offs and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin at the jointly administered Experimental and Clinical Research Center (ECRC), the Berlin Institute of Health (BIH) in Charité and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the Max Delbrück Center today employs 1,800 people and is 90% funded by the German federal government and 10% by the State of Berlin.

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