The Institute of Experimental Hematology investigates the biology of blood cell formation and function with a special focus on genetic cell modification as a new therapeutic modality.
Our research groups collaborate to form a portfolio ranging from the generation and expansion of stem cells to the control or enhancement of cell differentiation and function. We connect basic research and strong translational efforts in the field of molecular cell modification for the treatment of severe blood diseases, such as immune disorders and leukemia. The detection and prevention of risks associated with genetic cell modification and training of young scientists are important missions of our Institute.
The Institute of Experimental Hematology (IEH) contributes to strong research networks of Hannover Medical School, including the DFG-funded cluster of excellence REBIRTH http://www.rebirth-hannover.de/, the collaborative research center SFB738 http://www.sfb738.de/start.html, and the Integrated Research and Treatment Center for Transplantation Medicine (IFB-Tx) http://www.ifb-tx.de/. Furthermore, we participate in several network projects supported by the BMBF http://www.bmbf.de/de/1398.php, DAAD http://www.daad.de/de/index.html and Federal State of Lower Saxony https://r2n.eu as well as integrated projects of the EU Horizon 2020 (SCID-NET http://scidnet.eu; RECOMB http://www.recomb.eu/) and the ERC https://erc.europa.eu/. In the past, we have participated in other EU projects (PERSIST, CELL-PID).
From 2006-March 2013, the IEH was led by Prof. Dr. med. Christopher Baum. Since April 2013, the IEH is headed by Prof. Dr. med. Axel Schambach, PhD. Prof. Hildegard Büning was recently recruited to the IEH as a new W2 Professor to study the connections between infection biology and gene transfer mechanisms. Further group leaders are Prof. Dr. Jürgen Bode, Dr. Melanie Galla. Dr. Dirk Hoffmann, Dr. Olga Kustikova, Dr. Nico Lachmann, Dr. Tobias Maetzig, Dr. Johann Meyer, Prof. Dr. Thomas Moritz, PD Dr. Michael Morgan, Dr. Michael Rothe, and Dr. Dr. Adrian Schwarzer.
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
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.
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.