Biosafety of Gene Therapy

Ute Modlich, Reinhard Hämmerle, Sabine Knöß, Saskia Kohlscheen, Gabi Paul, Michael Rothe, Sabine Wintterle, Susanne Wolf

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. Such side effects need to be explored in suitable models in order to develop rules for safe and predictable gene therapy. In the development of novel preclinical assay systems, we focus on side effects related to random transgene insertion (insertional mutagenesis or genotoxicity) and transgene overexpression (“phenotoxicity”).   A cell culture model was developed that is based on the in vitro immortalisation of primary murine hematopoietic cells (In Vitro Immortalisation Assay), allowing the quantification of the genotoxic potential of integrating vectors. As a specific disease target we develop gene therapy for MPL deficiency. The associated human disease is termed congenital amegakaryocytic thrombocytopenia (CAMT), leading to life threatening aplastic anemia in early childhood. Gene therapy for MPL deficiency combines many of the most dangerous cofactors: A transgene that may act as a proto-oncogene, low stem cell numbers in patients, lack of an important receptor for stem cell activation in donor cells and high sensitivity of recipients to conditioning regimes. We aim to overcome these hurdles by employing improved vectors that restrict expression to its physiological site, and by exploring novel ways to generate and expand stem cells.

Selected own references: Heckl et al., Mol Ther 2012; Rothe et al., Gene Ther 2011; Heckl et al., 2011; Wicke et al., Mol Ther 2010

go to top