Mathematical modeling of individual clone dynamics for genetically modified stem cells within the hematopoietic system

• Applicant: Professor Dr. Ingo Röder
• Subject Area: Hematology, Oncology
• Term: from 2006 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 22749364

Due to their long-term reconstitution potential, tissue stem cells are used in gene therapeutic settings, where genetically engineered cells have to engraft and to long-term reconstitute specific tissues. However, recent observations demonstrate that gene transfer into hematopoietic stem cells (HSC) is potentially altering their competitive behavior and might induce genotoxicity. Currently, it is difficult to understand how small differences in cellular properties can become important effectors of clonal competition and to what extent clonal fluctuations can be influenced by interventions. The objective of this project is the application, refinement and validation of a previously developed mathematical model to describe individual clone dynamics in the HSC system with the ultimate aim to predict clonal contribution and persistence in vivo. Several experimental and clinical situations of murine, primate, and human hematopoiesis will be considered to derive validated reference models. Using computer simulations we will analyze the dynamic changes of clone number and size distributions and the influence of different cellular functions on the competitive potential of stem cell clones. These results will be used to optimize clone tracking strategies and to predict potential effects of new transfection and transplantation protocols.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1230: Mechanisms of Gene Vector Entry and Persistence
• Participating Person: Professor Dr. Markus Löffler