LOEWE-Research Group for (targeted) Gene Modification in Stem Cells
Research Overview and Research projects
Genetic modifications allow the generation of "designer" cells for cell and gene therapy. As stem cells are long-lived, possess self-renewal potential and the ability to form other cell types they are of particular interest for gene therapy. Our group is mainly interested in the modification of the blood systems via gene transfer to hematopoietic stem cells, but also the differentiation of blood cells from ES/iPS cells.
Improving the efficiency of genetic interventions goes hand in hand with exploring the nature and incidence of unwanted side effects. In hematopoietic gene therapy, side effects may originate from genetic damage following the insertion of the transgene, from interference of ectopic transgene expression with cellular signaling networks, and from cell culture dependent toxicity. Especially the treatment of stem cells harbors considerable risks as they have many pathways activated that also support the growth of cancer stem cells. The better understanding of the impact of genetic modifications on stem cells will help to preserve their phenotype and to improve gene therapeutic interventions.
Thrombopoietin-induced genes and pathways for the regeneration and maintenance of hematopoietic stem cells
HSC function is controlled by many factors including cytokines and their receptors, like the thrombopoietin (Thpo) receptor Mpl. Mpl was identified as the cellular homologue of the myeloproliferative leukemia virus oncogene (v-Mpl). Thpo/Mpl-signaling is involved in both, the expansion and the maintenance of HSCs. Furthermore, signaling via Mpl is crucial for megakaryocyte differentiation and platelet formation. Deregulation of MPL signaling causes hematological disorders. Activating mutations of MPL or mutations in downstream mediators of MPL signaling induce myeloproliferative disorders. MPL deficiency leads to thrombocytopenia and aplastic anemia.
We have demonstrated the correction of the Mpl-deficient phenotype in the Mpl knockout mouse model by lentiviral gene transfer. Especially interesting is the regeneration of HSC after Thpo/Mpl signaling was re-established. We analyzed the gene expression profile of regenerated HSC after Mpl gene therapy. Based on these analyses we could identify a Thpo/Mpl specific gene expression signature. Using lentiviral vectors expressing potential Mpl downstream targets in the Mpl-deficient mouse model we are searching for candidates that will allow to expand HSC and/or improve their functionality. Expression of the identified candidate genes may also support HSC that undergo in vitro genetic modifications. Furthermore, we aim for a deeper understanding of how Thpo/Mpl signaling controls HSC self-renewal and quiescence.
Modified platelets with enhanced function for vascular targeting
Platelets are anuclear cellular blood components of only 2µm size with an irrecoverable role in hemostasis, but also important functions in inflammation, angiogenesis, tumor growth and innate immunity. Furthermore, platelets play crucial roles in life threatening diseases such as thromboembolic events. Platelets are produced by megakaryocytes in the bone marrow, circulate through the blood stream within the blood vessels and maintain inactive (resting) until activated by environmental signals such as endothelial damage.
Platelets transport numerous proteins within their granules, which can be released after platelet activation, therefore act as "natural carriers". Theses natural characteristic of platelets make these cells an interesting target for cell therapy. We are proposing to develop modified platelets that would carry therapeutic proteins in their granules, which can be released after activation of platelets. This will create local milieus of therapeutic factors and will terminate with the end of the platelet life time. Because platelets will not persist long term, side effects induced by long term ectopic expression are not likely.
The modification of platelets has to be performed at earlier step of differentiation, the megakaryocyte, hematopoietic progenitor, HSC or even the pluripotent stem cell. For the genetic modification we use lentiviral vectors with transcriptional control that targets expression to megakaryocytes, or by the use of inducible vectors. By protein modifications we can supply synthetic growth factors, dominant-active or dominant–negative proteins and specifically target these proteins into the secretory platelet granules or to the cell surface. Furthermore, we envisage that platelets can be generated that respond to pharmaceutical inducers. Finally, we are interested in the in vitro production of platelets from ES/iPS cells.
Ute Modlich studied veterinary medicine at the Freie Universität Berlin. She obtained her doctoral degree in veterinary medicine (DVM) after research at the University Hospital Göttingen, and thereafter her PhD at the University of Oxford, Institute of Molecular Medicine, UK. After a postdoctoral training at the Heinrich-Pette-Institute in the laboratory of Prof. W. Ostertag, she joined the Dep. of Experimental Hematology at the Hannover Medical School headed by Prof. C. Baum where she entered the field of cell and gene therapy and became group leader in 2008. In 2013 she took the position as associate professor (W2) at the University of Frankfurt, Center for Cell and Gene Therapy, and established her group at the Paul-Ehrlich-Institute.