Our research aims at developing viruses and stem cells as therapeutic agents for the treatment of human inherited and acquired diseases with an emphasis on fundamental and pre-clinical research. The utility of developed gene delivery and stem cell technology in patients is tested in collaboration with clinical research groups within and outside the LUMC.
The virus biology research concentrates on the development and characterization of improved viral vectors for biomedical research in general, and gene therapy in particular. Four topics have our particular interest:
The goal of our "oncolytic virus" project is to develop viruses as anti-cancer agents. Two viruses that are relatively harmless to humans are used in this research line. The tropism of Adenoviruses, which normally cause only mild cold-like symptoms, is modified by inclusion of tumor-specific ligands in their capsid. In parallel human Reoviruses are generated that specifically kill tumor cells. Moreover the delivery of the oncolytic agents to the tumors has our interest, and here we focus on cell-based delivery. Our viruses are evaluated in models for prostate cancer, glioblastoma, liver cancer, and melanoma in collaboration with scientists in the Netherlands, France, Sweden, and the United Kingdom. In parallel, we study how tumor-seeking stem cells can be used for delivery of oncolytic viruses to metastatic tumor nodules.
The "immune evasion" project aims at reducing the acquired immune responses against the transgene products following therapeutic gene transfer. We evaluated an cis-acting inhibitor of proteasomal degradation derived from the Epstein-Barr virus nuclear antigen-1. Moreover, a new inhbitior sequence was identified in the LANA-1 protein from the Kaposi Sarcoma Herpes Virus (HHV-8). These inhibitors are used for preventing antigenic peptide generation from transgene products, and allow synthesis of antigenic proteins without the concomitant destruction of the cells by T-lymphocytes. More recently we evaluate trans-acting inhibitors of antigen presentation to protect cells from allo- and auto-reactive T cells.
Finally, we operate the ‘LUMC viral-vector facility’, which produces viral vectors for use by LUMC researchers. The facility provides lentivirus vectors for preclinical research within the LUMC. The facility also handles requests for clones of our 160.000-clone lentivirus-based short-hairpin library. The clones target each of 15.000 human and 15.000 mouse genes.
The stem cell activities focus on the forced differentiation of human stem and progenitor cells insulin-producing cells by heterologous expression of pancreas-specific transcription factors, respectively. In these studies both human mesenchymal stem cells and on a stem-cell population isolated from islets of Langerhans are studied. The effect of various culture conditions on the efficiency of differentiation of the stem cells may guide the development of optimized differentiation protocols.