Project Details
Projekt
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
Subject Area
Hematology, Oncology
Immunology
Immunology
Term
from 2018 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 398018062
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 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 affect B and T lymphopoiesis. They were chosen, because they can be cured by transplanting even small numbers of 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 availability of hematopoietic precursor cells (HSC) from RAG-SCID and HIGM1 patients. To overcome this limitation, we will apply our gene-editing strategy human to bone marrow-derived HSC and to multipotent hematopoietic progenitors derived from induced pluripotent stem cells (iPSCs), which can be generated from many human cell types. We will 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 the developmental potential of GE-LPs in vivo by transplanting the cells into novel mouse strains optimized for the engraftment and multilineage differentiation of human HSC. Our project is structured into five Work Packages (WPs; Fig. 1):1) To correct disease-causing mutations by gene editing technology in situ.2) To generate GE-LPs from patient-derived iPSCs3) To generation GE-LPs from patient-derived hematopoietic stem cells4) To validate B and T cell development from GE-LPs in vitro5) To evaluate the engraftment capacity and function of GE-LPs in vivoOur combined expertise will allow the functional validation of a GE-LPs based therapy both in vitro and in vivo. Several aspects of our approach have been already adapted to GMP conditions. Together with our proven experience in translating gene therapy to the clinic, this warrants the sustained and seamless transfer of the methodology developed in this project into clinical application. We expect, that our study will provide an innovative tailored and precise gene-based treatment of PIDs.
DFG Programme
Research Grants
International Connection
Belgium, France, Italy
Cooperation Partners
Professorin Dr. Isabelle André- Schmutz; Professor Dr. Luigi Naldini; Professor Dr. Tom Taghon
