Project Details
Projekt
Ex vivo Identification of Specific Gene Vector Capsids for Tumor-targeted Gene Therapy with Adeno-associated Viral Vectors
Subject Area
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 523830300
Despite all unquestionable advances in recent years, cancer remains one of the biggest challenges in healthcare and biomedical research. Further improvement of the therapeutic armamentarium is urgently needed and gene therapy may a suitable strategy to meet this demand. Currently, however, intravascular administration of anti-tumor gene therapy vectors in human patients is especially limited by a lack of tumor-targeted vector systems. Adeno-associated viruses (AAV) are among the most widely used vector systems in a variety of experimental and clinical settings but their tropism does not allow for selective gene transfer into tumor tissue upon intravenous injection. Based on our extensive previous work, we will use random peptide libraries displayed on the AAV capsid surface, thereby broadening the tropism of AAV by generating millions of different vector capsids with potential affinity for previously non-compatible cell surface receptors. For the first time, such libraries displaying peptides in several sizes on the surface of AAV2 and AAV9 serotypes will be screened ex vivo over multiple subsequent selection rounds by perfusion of whole or partial en-bloc organs (kidney and colon) surgically removed from cancer patients. Vector capsids enrich in tumor but not normal tissue will be amplified, identified und subsequently evaluated as single clones regarding their specific tropism towards tumor but not normal tissue. The aim of this project is therefore to identify novel clinically relevant AAV capsid variants with selectivity for tumor tissue and /or tumor-associated endothelial cells upon intravascular administration. AAV capsid mutants isolated by our ex vivo screening approach in human tissue will likely outperform previous capsid variants isolated from cancer tissue in mouse models which may have failed to translate into the clinic due to interspecies variability.
DFG Programme
Research Grants
