BACKGROUND: XLP1 arises from mutations in the SH2D1A gene encoding SAP, an adaptor protein expressed in T, NK and NKT cells. Defects lead to abnormalities of T and NK cell cytotoxicity and T cell dependent humoral function. Clinical manifestations include haemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinaemia. Curative treatment is limited to haematopoietic stem cell transplant with outcome reliant on a good donor match. OBJECTIVES: As most symptoms arise from defective T cell function, we investigated whether transfer of SAP gene corrected T cells could reconstitute known effector cell defects. METHODS: CD3+ lymphocytes from sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sub-lethally irradiated sap-deficient recipients. Following immunisation with the T-dependent antigen NP-CGG, recovery of humoral function was evaluated through germinal centre formation and antigen specific responses. To efficiently transduce patient CD3+ cells, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated using in vitro cytotoxicity and TFH cell function assays, alongside tumour clearance in an in vivo LCL lymphoma xenograft model. RESULTS: In sap-deficient mice, 20-40% engraftment of gene modified T cells led to significant recovery of germinal centre formation and NP-specific antibody responses. Gene corrected patient T cells demonstrated improved cytotoxicity and TFH cell function in vitro. Adoptive transfer of gene corrected patient CTLs reduced tumour burden to a level comparable with healthy donor CTLs in an in vivo lymphoma model. CONCLUSIONS: These data demonstrate that autologous T cell gene therapy corrects SAP dependent defects and may offer an alternative therapeutic option for XLP1 patients
