Diagram of CAR-T cell generation. On the left, manufactured CAR-T cells are injected. On the right, a gene shuttle selectively introduces the genetic information for CAR into T-cells.
Source: EMBO Mol Med
Viruses have evolved as particles that are optimally adapted to penetrate cells and transfer their genetic material. Clinical applications of gene therapy have been structured accordingly and are currently based on vectors derived from lentiviruses (LV) or adeno-associated virus (AAV). The COVID-19 pandemic led to non-viral systems based on lipid nanoparticles (LNPs) becoming another focus of gene therapy. We are researching the efficiency and safety of all these gene transfer vectors, especially with regard to applications in cancer immunotherapy using chimeric antigen receptors (CARs). We develop mouse models to predict possible side effects of CAR-T cells. With the help of specifically-targeted vectors for human T lymphocytes, the research group was the first in the world to succeed at producing CAR-T cells directly in the organism and to prove their effectiveness.
Receptor-targeted vectors are key to in vivo generation of CAR-T cells. Such vectors use a target cell receptor of choice and thus become highly selective for therapy-relevant cells. The underlying technology was developed by this research group and is applied to all three types of vector particles mentioned above. The technology is applied by using targeted point mutations to interrupt natural receptor use. Presenting high-affinity ligands such as DARPins (designed ankyrin repeat proteins) allows for the use of the desired receptor.
Receptor-specific precision gene vectors: Receptor binding structures – scFvs or DARPins – are presented on the surface of the lentiviral or AAV precision gene vectors. These structures direct the gene vectors to the therapy-relevant cells.
Source: Paul-Ehrlich-Institut
The generated vectors are studied for their gene transfer activity and target cell specificity in vitro on cell lines, primary cells, and organoid cultures, in vivo on humanised mouse models. In vivo, the focus is on the biodistribution of vector particles and the identification of new therapeutic strategies that open up through selective gene transfer. The projects include fundamental work on the technology as well as applications of the generated vector systems for gene function studies and novel therapeutic approaches.
Professor Dr Christian Buchholz
Publications
Phone: +49 6103 77 4011
Email: Christian.Buchholz@pei.de
Dr Jessica Hartmann
Phone: +49 6103 77 4226
Email: Jessica.Hartmann@pei.de
Updated: 04.08.2023
