Development of novel therapeutic approaches for primary immunodeficiency. (360G-Wellcome-090233_Z_09_Z)

1. Development of novel therapeutic approaches for primary immunodeficiency: We will develop new gene transfer vectors for reduced mutagenicity but also for enhanced tissue-specific activity. These will be evaluated in cell culture and murine model systems. We will also develop gene correction strategies, and application of alternative cellular targets based on reprogrammed somatic cells. Ongoing clinical trials will further inform areas of development and potential for broadened application to other disease candidates. 2. Studies on the Wiskott-Aldrich Syndrome Protein (WASp) and functionality of the immune system: we will determine the significance of WASp activation for functionality in murine model systems, both in terms of actin polymerising activity, but also protein stability and turnover. We will study human mutant forms of WASp that enable constitutive activation of actin polymerisation through disruption of autoinhibition, and will characterise the mechanisms of cell cycle a nd cytokinesis defects. We will study the role of WASp during formation of the immunological synapse, and during celll trafficking focussing primarily on the contribution of dendritic cells.