T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations

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Background: Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs. Objective: We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models. Methods: We developed a gammaretroviral vector to transduce murine CD8 T cells in the Prf−/− mouse model. To verify functional correction of Prf−/− CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope–transfected murine lung carcinoma cell tumor model. Furthermore, we challenged gene-corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1-encoding lentiviral vector to study restoration of cytotoxicity in human cells. Results: We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene-corrected Prf−/− CD8 T cells into Prf−/− mice. In the tumor model infusion of Prf−/− gene–corrected CD8 T cells eliminated the tumor as efficiently as transplantation of wild-type CD8 T cells. Similarly, mice reconstituted with gene-corrected Prf−/− CD8 T cells displayed complete protection from the HLH phenotype after infection with LCMV. Patients’ cells showed correction of cytotoxicity in human CD8 T cells after transduction. Conclusion: These data demonstrate the potential application of T-cell gene therapy in reconstituting cytotoxic function and protection against HLH in the setting of perforin deficiency.




Ghosh, S., Carmo, M., Calero-Garcia, M., Ricciardelli, I., Bustamante Ogando, J. C., Blundell, M. P., … Gaspar, H. B. (2018). T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. Journal of Allergy and Clinical Immunology, 142(3), 904-913.e3. https://doi.org/10.1016/j.jaci.2017.11.050

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