Regulated SAP gene transfer for correction of X-linked lymphoproliferative disease. (360G-Wellcome-082159_Z_07_Z)

X-linked lymphoproliferative disease (XLP) is a genetic disorder resulting in immunedysregulation, typically following Epstein-Barr virus (EBV) infection. Affected boys suffer from fulminant infectious mononucleosis, malignant lymphoma or hypogammaglobulinaemia. The defective gene is SH2D1A, which encodes for SAP protein (SLAM associated protein, involved in regulation of immune cell signalling) expressed in T and NK cells but not in primary B cells. Current management involves haematopoietic stem cell transplant but success is dependent on a good donor match and absence of active infection at transplant. Somatic gene therapy can correct certain forms of immunedeficiency and offers a potential cure for XLP. However, dysregulated gene expression is potentially harmful. In this study we aim to develop vectors expressing SAP in a regulated manner allowing correction of the disease phenotype without untoward side effects. Lentiviral vectors will be generated encoding SAP under the regulation of recently defined SAP promoter elements or the CD2 promoter. These vectors will initially be tested for physiological patterns of expression and function prior to use in correcting cellular models of SAP deficiency and to recomplement SAP in an siRNA knockdown SAP deficiency model. We also aim to correct a murine model of XLP using the optimal SAP lentiviral construct.