Area C: Clinical Translation and Regenerative Products

The Area C provides the necessary infrastructure for translation of novel products or therapies derived from basic research by REBIRTH scientists into clinical settings. It offers a unique blend of know-how with regard to production of large-animal models, determination of (epi)genomic stability, pathology, upscaling of stem cell production, long-term storage of biological material, and clinical trial management, and even addresses the ethical and legal aspects of regenerative medicine. This should help to move regenerative medicine closer to clinical application, which is a major goal of REBIRTH.

Area C comprises Collaborative Research Units (CRU) 9 'Regenerative Pathology and Pharmacotoxicology' and CRU 10 'Regenerative Products, Clinical Trials', Ethics and Law', with six and seven research groups, respectively. Groups in Area C have a dense established network of collaborations, both within the Cluster and with external institutions, and possess the expertise that is critical for the success of the planned experiments within REBIRTH II. Members of Area C have published many papers in peer-reviewed journals, frequently as joint publications between several REBIRTH partners, some of which have appeared in prominent scientific journals. Furthermore, groups in Area C have received a large amount of competitive research funding and have been able to attract a considerable number of talented young scientists, indicating the excellent reputation that the Cluster enjoys in the outside world. The expertise provided in Area C should enable findings to be transferred from basic research into clinical application (translational approach).

CRU 9: Regenerative Pathology and Pharmacotoxicology

CRU 9.1 is a new addition to REBIRTH II. The goal is to provide new large-animal models. Functional protocols for somatic cell nuclear transfer (SCNT) and the recent availability of novel tools for precise genetic engineering, including zinc-finger nucleases (ZFNs), TALEN, CRISP-Cas and transposons, provide new options for effective production of transgenic animals. The main aim of this consortium consisting of various REBIRTH groups, led by ING/FLI, Mariensee, is to produce human cardiomyocytes and hepatocytes in the domestic pig for use in cell therapies with human patients. This will entail challenging experiments involving chimera formation between porcine and human cells. Another goal is the production of a useful disease model, specifically pigs showing symptoms of familial hypertrophic cardiomyopathy (FHC). This work has already been started and pregnancies from transgenic porcine fibroblasts carrying the FHC mutation induced by TALE-nuclease technology have been obtained. The group in Mariensee is closely associated with the recently established DFG-funded Transregio SFB ‘Biology of xenogenic cells - from bench to bedside’ that will move xenotransplantation closer to clinical application. This further strengthens the transplantation expertise of Hannover Medical School (MHH).

An important aspect of treatment with novel cellular therapies that will emerge from basic research in REBIRTH II is to ensure the safety of the products. Research units 9.2 and 9.3 have specific expertise in pathology of animal models and teratoma diagnosis, and will make this know-how available to the REBIRTH community. Another important aspect of safety is genomic stability. This is specifically addressed in research units 9.5 and 9.6, which provide technologies for cytogenetic and genomic profiling (including banding analysis, quantification of DNA repair, multicolour fluorescence in situ hybridization and telomere length measurement) to detect potential genetic instabilities. The chief goal will be to obtain insight into the underlying mechanisms of genetic instability and the factors triggering expansion of dominant clones after genetic modification of stem cells, ultimately to prevent malignant transformation. In addition, research unit 9.4 looks at specific aspects of preclinical safety and toxicology associated with gene therapy trials (ITEM, Fraunhofer).

CRU 10: Regenerative Products, Clinical Trials', Ethics and Law

An important prerequisite for clinical application of novel cellular therapies is mass production of therapeutic cells, including bioactive macromolecules, pluripotent stem cells and their derivatives. REBIRTH II has outstanding expertise in these areas, based on previous achievements such as the production of endotoxin-free cytokines and development of the prototype of a suspension culture system for human pluripotent stem cells. An industrial collaboration with regard to process development and reactor technology has already been established. Clinical application of novel cellular therapies requires reliable technology for banking of cells or at least to stabilize tissues and macromolecular assemblies. These aspects are addressed in research units 10.3 and 10.4, located at the Leibniz University of Hannover. The research will include safety aspects, effects of long-term storage on the stability of cells and tissues, and the efficiency of the freezing process.

An important prerequisite for clinical application of products derived from research in REBIRTH II is to provide services assisting with all the required aspects of biological-safety evaluation of medical devices and novel therapies. Research unit 10.5 specifically addresses these aspects, and the BioMedimplant facility provides the full range of methods for testing biological safety of medical products based on tissue engineering and nanomaterial. Research unit 10.6 has in-depth experience in clinical trial management and will make this expertise available for all products/therapies emerging from REBIRTH II activities. REBIRTH II acknowledges the ethical and legal dimension of the work that is done within the Cluster. Research unit 10.7 specifically explores these novel ethical questions; it will provide advice on legal aspects and stimulate the ethical and moral debate on cellular therapie.