Biomedical Research: Engineered C57BL/6 as Mouse Models for the Study of Treatments for Hutchinson-Gilford Progeria Syndrome (HGPS), and HER2-positive cancers.

This thesis focuses on two engineered C57BL/6 mice models used to study treatments for Progera Syndrome and HER2-positive cancers. The first study, conducted in collaboration with the National Research Council, Institute of Molecular Genetics - Unit of Bologna, is on LmnaG609G transgenic mice homologous for the genetic cause of Progeria Syndrome. The objective was to describe the model, giving information on the housing, breeding, welfare and progression of the disease. Similarities and differences between the model and human patients were highlighted and the acquired data will be essential in programming future studies using this animal model. Following this, a preliminary study was conducted on the mice, using a treatment of all-trans retinoic acid (0.4 mg/kg) combined with low doses of rapamycin (1 mg/kg) administered twice weekly intraperitoneally, in order to evaluate whether the mice's lifespan was improved. Results comparing treated and untreated groups were not significant. However, the animal groups were small in number and only males were considered, so future research will be needed. The second study reports the use of HER2 tolerant transgenic mice to investigate the efficacy of immunotherapy with oncolytic viruses. This study was performed in collaboration with the Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna. The mouse demonstrated to be a reliable model since it enabled the development of implanted HER2 cancer and allowed the virus replication within the tumour. Animals did not show any side effects and the safe profile of the virus was confirmed. To date we tested the efficacy of two viruses: R-LM113 and R-LM113-mIL-12. The latter gave better results, underlining the importance of the immune system in oncology and immune competent models in oncology research. In conclusion, we can state that both animal models considered in this thesis have demonstrated their appropriateness for testing specific therapies.