by Researchers at the Max Delbrück Center have discovered a groundbreaking way to treat hereditary genetic defects that cause an exaggerated immune response. Using the CRISPR-Cas9 gene-editing tool, they were able to correct these defects and normalize the immune response in a study published in Science Immunology.
The focus of the study was familial hemophagocytic lymphohistiocytosis (FHL), a rare disease of the immune system that primarily affects infants and young children. It is caused by various gene mutations that impair the function of cytotoxic T cells, a group of immune cells responsible for eliminating virus-infected or abnormal cells.
In FHL patients, the cytotoxic T cells are unable to eliminate infected cells, leading to an out-of-control immune response. This excessive inflammation affects the entire body and can be life-threatening, especially when triggered by infections such as the Epstein-Barr virus.
Current treatment for FHL includes chemotherapy, immunosuppression, and bone marrow transplantation. However, the mortality rate for this disease remains high. Professor Klaus Rajewsky, the head of the Immune Regulation and Cancer Lab at the Max Delbrück Center, and his team sought to develop a more effective therapeutic strategy.
Using the CRISPR-Cas9 gene-editing tool, the researchers successfully repaired defective T cells from mice and two critically ill infants. The repaired cytotoxic T cells returned to normal function, resulting in the recovery of the mice from hemophagocytic lymphohistiocytosis.
The study initially used mice to mimic EBV infections. The researchers altered a gene called perforin to model the common genetic defect found in FHL patients. The altered mice experienced uncontrolled multiplication of B cells and the development of hemophagocytic lymphohistiocytosis due to the inability of defective cytotoxic T cells to eliminate them.
The team collected T memory stem cells, which are long-lived T cells capable of maturing into active cytotoxic T cells, from the mice’s blood. Using the CRISPR-Cas9 gene-editing tool, they repaired the defective perforin gene in these memory T cells and re-injected them into the mice. This resulted in a calming of the immune response and the disappearance of symptoms.
To test the effectiveness of their strategy in humans, the researchers obtained blood samples from two sick infants. One of them had a defective perforin gene, while the other had a different defective gene. The gene repair technique used in the study was proven to be more precise than previous methods, and the T cells remained virtually unchanged after undergoing gene editing.
Dr. Xun Li, the first author of the paper, highlighted the fascinating ability of memory T cells to be multiplied and repaired from even a small amount of blood. This advancement in gene editing holds great promise for the treatment of hereditary genetic defects that affect the immune system.
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1. Source: Coherent Market Insights, Public sources, Desk research
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