21 February 2024

CRISPR-Cas9 editing could one day be used to treat familial haemophagocytic lymphohistiocytosis (FHL), scientists have reported.

The technique has been used successfully in a mouse model of the disease. Laboratory analysis of cells from human patients have also supported the effectiveness of the gene editing technique, according to the German study.

Researchers at the Max Delbrück Centre of the Helmholtz Association have reported their findings in the journal Science Immunology.

Familial haemophagocytic lymphohistiocytosis (FHL) affects infants under the age of 18 months and is frequently fatal. It is caused by gene mutations that prevent cytotoxic T cells from functioning correctly.

The researchers caution that their studies do not yet indicate how long treatment will remain effective.

For the mouse study, the researchers altered a gene called perforin so that its function was completely lost or severely compromised – a common genetic defect in patients with FHL. They then elicited a condition resembling an EBV infection in the animals. The affected B cells multiplied uncontrollably because the defective cytotoxic T cells were unable to eliminate them.

CRISPR-Cas9 was then used to repair memory T cells and return them to the mice, correcting the defect in the perforin gene and prevent severe disease.

Separately, the team also showed that correction of defective genes was feasible in human T cells donated by two FHL patients, restoring the T cells’ cytotoxic ability in lab tests.

Lead researcher Professor Klaus Rajewsky said: “Doctors treat FHL with a combination of chemotherapy, immunosuppression and bone marrow transplantation, but many children still die of the disease. We very much hope that our mechanism of action is a breakthrough in treating FHL, either to gain more time for a successful bone marrow transplant or even as a treatment itself.”

Researcher Dr Xun Li said: “Our gene repair technique is more precise than previous methods, and the T cells are virtually unchanged after undergoing gene editing. It was also fascinating to see how effectively the memory T cells could be multiplied and repaired from even a small amount of blood.”


Li X, Wirtz T, Weber T, Lebedin M, Lowenstein ED, Sommermann T, Zach A, Yasuda T, de la Rosa K, Chu VT, Schulte JH, Müller I, Kocks C, Rajewsky K. (2024)Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis.” Science  Immunology, doi: 10.1126/sciimmunol.adi0042.

Link: https://www.science.org/doi/10.1126/sciimmunol.adi0042

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