Scientific goals

The unifying topic of our research is to understand the principles governing induced and pathologic regeneration of blood cell formation (hematopoiesis and the hematopoietic niche). Our scientific goals are

1. the analysis of the mechanisms underlying proliferation and differentiation of pluripotent cells to hematopoietic stem cells,

2. the discovery of novel pathways that support self-renewal and competitive fitness of normal and malignant hematopoietic stem cells,

3. the development of novel cell and gene therapeutics for inherited or acquired disorders, based on molecular insights into mechanisms of vector-host interactions,

4. the implementation of rational genome engineering strategies in somatic stem cells to characterize and treat inherited or acquired disorders of the hematopoietic system, based on molecular insights into the cellular DNA repair machinery and the processes that govern the differentiation and de-differentiation between committed somatic cells and pluripotent stem cells.

We attempt to combine biological and technological progress with a detailed risk assessment of novel therapeutic approaches. The experimental scope of our institute ranges from investigation of basic mechanisms of genetic cell modification to implementation of translational projects designed to establish improved conditions for clinical trials using advanced cellular therapeutics.

Research at the Institute of Experimental Hematology (IEH)

The ongoing improvement of gene transfer technologies for hematopoietic and other cell types has a great impact for the application in clinical trials. Therefore, the design and evaluation of novel safety-modified retroviral vectors, derived from gamma-, lenti- and alpharetroviruses (Melanie Galla, Axel Schambach), adeno-associated virus (AAV) (Hildegard Büning) and chromosome-based vectors to support recombinase-mediated cassette exchange (RMCE) techniques (Jürgen Bode) are major focuses in our institute.

These technologies can be exploited to design entirely novel tools for gene therapy and to systematically modify ES- and iPS- cells. Our vector platform has been successfully used to explore novel strategies to generate/regenerate and expand stem cells (Thomas Moritz, Axel Schambach). For example, patient-specific iPSC can be exploited to model diseases (e.g. primary immunodeficiencies, X-linked chronic granulomatous disease, hereditary pulmonary alveolar proteinosis) and to test novel molecular medicine interventions, such as gene therapy, differentiation into hematopoietic stem and/or progenitor cells, control of hematopoietic stem cell expansion after transplantation, generation of novel transplantation strategies (Dirk Hoffmann, Nico Lachmann).

Our institute also uses designer nucleases, such as TALE nucleases (TALENs) or clustered regularly interspaced short palindromic repeats (CRISPR) associated 9 (Cas9) to develop rational genome editing approaches (Axel Schambach in collaboration with T. Cathomen (Freiburg, Germany) and E. Charpentier (Berlin, Germany). In addition to the obvious clinical potential of these strategies, this work is also expected to improve our understanding of DNA repair in somatic stem cells.

A major challenge of gene therapy is insertional transformation of hematopoietic stem cells due to up- or down-regulation of genes critical for hematopoiesis. In collaboration with our colleague B. Fehse (Hamburg, Germany), our institute seeks to elucidate the mechanisms that cause these events (Olga Kustikova). Our work in this area includes identification of novel genes and pathways that improve the competitive fitness of normal and malignant hematopoietic stem cells. For the analysis of side effects related to semi-random vector insertion (insertional mutagenesis or genotoxicity) and transgene overexpression (“phenotoxicity”), the IEH utilizes the in vitro immortalization assay (IVIM) to analyze the risks associated with current vector systems. We constantly aim to develop new assays for better preclinical risk assessment (Michael Rothe, Axel Schambach).

To better understand the mechanisms driving cell transformation and to develop novel strategies to combat blood cancers, our institute strives to define molecular mechanisms that lead to aberrant cellular signaling (Johann Meyer, Michael Morgan, Adrian Schwarzer). In the hematopoietic system, cell processes such as proliferation, differentiation and apoptosis are tightly controlled by cytokines and their corresponding receptors. Therefore, we investigate receptor biology and signal transduction by engineering cytokine receptor variants and employing small molecule inhibitors designed to target specific signaling modules. Additionally, our institute is actively involved in enhancing tumor-specific cytotoxicity of natural killer (NK) and T cells by equipping these immune cells with chimeric antigen receptors (CARs) designed to recognize tumor-specific antigens.

In summary, the Institute of Experimental Hematology aims to produce and improve cell modification technologies to develop useful cell therapy approaches. Key interests of our institute include the understanding of vector-host interactions regulating transcriptional and post-transcriptional events of transgene expression, and the analysis of post-entry mechanisms of retroviral particle processing. Following detailed analyses in preclinical model systems, a number of national and international collaborators have initiated clinical trials with vectors developed by our team, e.g. the recent SCID-X1 trial in Boston, Paris and London. Additional clinical trials will be initiated in the future.