Joint Transnational Call 2017 (JTC2017)


Our project provides a new gene and cell therapy-based strategy to treat severe combined immunodeficiency (RAG-SCID) and hyper-IgM syndrome 1 (HIGM1). Both rare primary immunodeficiencies (PIDs) manifest during the first year of life and are caused by mutations in RAG1 and CD40LG. The expression of both genes is tightly regulated. Therefore, the genetic defects cannot be treated by classical gene transfer methodology. Our strategy is therefore based on the correction of RAG1 and CD40LG mutations by a gene-editing approach which is followed by the adoptive transfer of gene-edited lymphoid progenitor cells (GE-LP). Both genetic defects affecting B and T lymphopoiesis were chosen because they can be cured by transplanting even small numbers of corrected lymphoid progenitor cells. To correct RAG1 and CD40LG mutations in situ we will apply nuclease-mediated homologous recombination as this restores gene function while retaining the endogenous control of gene expression. Gene therapy options are also limited by the access to hematopoietic precursor cells (HSC) from the young RAG-SCID and HIGM1 patients. To overcome this limitation, we will compare our gene-editing strategy human in bone marrowderived HSC and in multipotent hematopoietic progenitors derived from induced pluripotent stem cells (iPSCs), which can be generated from almost any human cell type. We will first validate gene-editing of RAG1 and CD40LG mutations in human HSC in vitro by measuring both functionality and molecular signatures of GE-LPs. We will then evaluate in vivo functionality of GE-LPs using unique innovative mouse tools that are optimized for the engraftment of human human hematopoietic stem and progenitor cells (HSPC) populations and allow for multilineage differentiation read-out because the generation of all hematopoietic lineages is strongly supported in these NSGW41hIL7tg mice.

  • Naldini, Luigi (Coordinator)
    Ospedale San Raffaele [ITALY]
  • André-Schmutz, Isabelle
    Institut National de la Santé de la Recherche Médicale [FRANCE]
  • Waskow, Claudia
    Technische Universität Dresden [GERMANY]
  • Eibel, Hermann
    Universitäetsklinikum Freiburg [GERMANY]
  • Taghon, Tom
    Ghent Univeristy [BELGIUM]