Genome editing has been used to successfully correct genetic defects in a mouse model of a fatal hereditary disease familial hemophagocytic lymphohistiocytosis (FHL).
A team at the Max Delbrück Centre for Molecular Medicine in Berlin, Germany, used CRISPR/Cas9 genome editing to treat mouse models of FHL. The researchers hope the study paves the way for a less invasive and longer-lasting treatment for the disease.
Professor Klaus Rajewsky, who led the study, said: 'We very much hope that our mechanism of action is a leap forward in treating FHL, either to gain more time for a successful bone marrow transplant or even as a treatment itself.'
FHL is an often fatal hereditary disease, where defective cytotoxic (or 'killer') T cells cause a dangerously out of control immune response that can lead to cytokine storms and multiple organ failure. It mostly affects infants under the age of 18 months, and is treated with a combination of chemotherapy, bone marrow transplantation and immunosuppression.
Published in Science Immunology, the research team used CRISPR/Cas9 genome editing to replace inherited defective T cell genes with functional copies. As the symptoms of FHL are often triggered by a viral infection, the team manipulated the cytotoxic T cells of mice infected with Epstein-Barr virus (EBV).
The mice carried defective copies of the gene for perforin – a critical protein released by T cells to kill infected host cells – which is a common cause of FHL in humans. After taking blood samples, researchers used a harmless virus to insert functional copies of the genes via CRISPR/Cas9 to T cells and readministered them to the mice, whose symptoms of FHL disappeared.
The results were replicated in T cells from the blood of two FHL patients. Here, genetic defects in both perforin and another protein that impairs T cell function were corrected. Although the cells were not reinfused and used to treat the patients, the T cells regained normal function in vitro, serving as an important proof-of-principle for treating FHL in humans. Furthermore, the technique was successful in the memory subset of T cells, which can last for years and may therefore confer long-term protection.
Professor Rajewsky's team admits that it is not clear exactly how long protection from genome-edited cells could last.
'Since the T memory stem cells remain in the body for a long time, we hope the therapy provides long-term or even permanent protection,' commented Dr Christine Kocks, contributing author to the study. 'It is also conceivable that patients could be treated with their repaired T cells over and over again.'
Sources and References
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Gene editing precisely repairs immune cells
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Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis
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Gene editing of immune cells offers hope for rare diseases, study shows
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Pioneering CRISPR-Cas9 Gene-Editing Offers Hope for Fatal Immune Disorder in Children
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AAV-CRISPR/Cas9: An imminent treatment for familial hemophagocytic lymphohistiocytosis?
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