2. Academic Validation
  3. Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis

Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis

  • Sci Immunol. 2024 Feb 2;9(92):eadi0042. doi: 10.1126/sciimmunol.adi0042.
Xun Li 1,  Tristan Wirtz 1,  Timm Weber 1,  Mikhail Lebedin 2 3,  Elijah D Lowenstein 4,  Thomas Sommermann 1,  Andreas Zach 1 3,  Tomoharu Yasuda 1,  Kathrin de la Rosa 2 5,  Van Trung Chu 1 6,  Johannes H Schulte 7,  Ingo Müller 8,  Christine Kocks 1 4,  Klaus Rajewsky 1
Affiliations

Affiliations

  • 1 Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
  • 2 Immune Mechanisms and Human Antibodies, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
  • 3 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany.
  • 4 Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
  • 5 Center of Biological Design, Berlin Institute of Health (BIH) at Charité, 13125 Berlin, Germany.
  • 6 Genome Engineering & Disease Models, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
  • 7 Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany.
  • 8 Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
PMID: 38306418 DOI: 10.1126/sciimmunol.adi0042
Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL is caused by inactivating mutations in proteins that regulate cellular immunity. Here, we used an adeno-associated virus-based CRISPR-Cas9 system with an inhibitor of nonhomologous end joining to repair such mutations in potentially long-lived T cells ex vivo. Repaired CD8 memory T cells efficiently cured lethal hyperinflammation in a mouse model of Epstein-Barr virus-triggered FHL2, a subtype caused by perforin-1 (Prf1) deficiency. Furthermore, repair of PRF1 and Munc13-4 (UNC13D)-whose deficiency causes the FHL subtype FHL3-in mutant memory T cells from two critically ill patients with FHL restored T cell cytotoxicity. These results provide a starting point for the treatment of genetic T cell immune dysregulation syndromes with repaired autologous T cells.

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Products
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    Product Name
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  • HY-101570
    99.70%, DNA-PK Inhibitor