Gene Repair in Autologous T Cells Rescues Infants with Immune Dysregulation

A team of researchers led by Professor Klaus Rajewsky from the Max Delbrück Center has reported success in correcting hereditary genetic defects causing an exaggerated immune response, particularly in the case of Familial Hemophagocytic Lymphohistiocytosis (FHL), a rare and severe immune deficiency. The study, published in Science Immunology, utilized the CRISPR-Cas9 gene-editing tool to repair defective T cells in mice and critically ill infants with FHL, restoring normal immune function. This novel therapeutic strategy shows promise in treating genetic T cell immune dysregulation syndromes by repairing autologous T cells.

Key Points:

1. Familial Hemophagocytic Lymphohistiocytosis (FHL): FHL is a rare and severe immune deficiency characterized by systemic hyperinflammation, often affecting infants and young children. It has a high mortality rate and is caused by various gene mutations that impair the function of cytotoxic T cells, leading to an exaggerated immune response.
2. CRISPR-Cas9 Gene Editing: The researchers employed the CRISPR-Cas9 gene-editing tool to repair defective T cells associated with FHL. Specifically, the study focused on mice with a genetic defect in the perforin gene, a common mutation in patients with FHL.
3. Mimicking Epstein-Barr Virus (EBV) Infections: In mice with altered perforin genes mimicking FHL conditions, the researchers induced a condition similar to an EBV infection. This led to uncontrolled multiplication of B cells due to defective cytotoxic T cells, resulting in hemophagocytic lymphohistiocytosis.
4. Collection and Repair of T Memory Stem Cells: T memory stem cells, representing long-lived T cells, were collected from the blood of the mice. The CRISPR-Cas9 tool was then utilized to repair the defective perforin gene in these memory T cells.
5. Injections of Corrected Cells: The repaired T memory stem cells were injected back into the mice. The corrected cells matured into active cytotoxic T cells, and the immune response in the mice normalized, leading to the resolution of hemophagocytic lymphohistiocytosis symptoms.
6. Human Application: Blood samples from two critically ill infants with FHL were used to test the gene repair strategy in humans. One infant had a defective perforin gene, while the other had a different defective gene. The technique demonstrated precision and efficacy in repairing T cells from human samples.
7. Promising Therapeutic Strategy: The study suggests that repairing autologous T cells using CRISPR-Cas9 is a promising therapeutic strategy for treating genetic T cell immune dysregulation syndromes, including FHL. The precision of the gene repair technique and the successful normalization of immune function in mice and human T cells highlight the potential of this approach.
8. Considerations for Future Research: While the current findings show successful correction of T cells and resolution of symptoms in mice and infants, further research is needed to determine the long-term effectiveness and safety of the gene repair strategy. Additionally, the study opens avenues for exploring similar approaches in treating other genetic T cell immune dysregulation syndromes.

Conclusion:

The research demonstrates the successful application of the CRISPR-Cas9 gene-editing tool to repair defective T cells associated with Familial Hemophagocytic Lymphohistiocytosis (FHL), offering a potential therapeutic strategy for treating severe immune deficiencies. The precision and efficacy observed in repairing autologous T cells, both in mice and human samples, provide a foundation for further investigations into gene repair as a treatment for genetic T cell immune dysregulation syndromes.

More information: Xun Li et al, Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis, Science Immunology (2024). DOI: 10.1126/sciimmunol.adi0042. www.science.org/doi/10.1126/sciimmunol.adi0042