PhD defence O.A. Diaz Arguello

Development of adenoviral vectors armed with TNF-related therapeutic proteins for gene therapy

The introduction, removal, or addition of genetic materials to treat a disease is considered gene therapy. Thus, various gene therapies have been developed to treat monogenic diseases, infectious diseases, inflammation, and cancer by delivering genetic material into the patients' cells using vectors, such as viruses. The use of adenoviral vectors to deliver therapeutic genes has the advantage of continuous protein production, which helps avoid repeated administration. This thesis aimed to develop adenoviral vectors carrying the genes encoding the Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL) and the receptor activator of NF-B ligand (RANKL) for their use as treatments for cancer or fibrosis. Both proteins belong to the TNF family; TRAIL is capable of apoptosis induction in cancer cells without harming healthy cells, while RANKL has therapeutic implications in cancer and fibrosis.Adenoviral-secreted fusion proteins containing an epidermal growth factor receptor (EGFR)-targeted TRAIL were capable of reducing the cell viability of cancer cells without affecting normal non-transformed cells. More importantly, the fusion proteins showed a higher apoptotic effect than the combined treatment of soluble TRAIL and anti-EGFR.Regarding the RANKL-armed adenoviral vectors, long-term production and secretion of the proteins were achieved. In addition, the RANKL proteins were specifically able to activate anti-fibrotic genes. These results show the potential of adenoviral vectors for the treatment of cancer and inflammation.

Promotores Prof.dr. H.J. Haisma and Prof.dr. F.J. Dekker