DEVELOPMENT OF RECOMBINANT AAV VECTORS FOR HUMAN GENE THERAPY: MOLECULAR DETERMINANTS GOVERNING VIRAL TRANSDUCTION

The over 500 gene therapy clinical trials so far conducted have clearly indicated that several improvements have to be introduced before important clinical results are achieved. In particular, the issue of transferring genes with high efficiency appears to be still problematic. Therefore, the development of novel efficient vectors is mandatory. This research project is aimed at studying a class of gene therapy vectors based on the AAV virus. This is a small virus that is largely diffused in the population and has never been found associated to any disease. Our laboratory is the only one in Italy to have developed a protocol for the production of high titer AAV vectors to be used in experimental animals. In collaboration with other Italian groups we developed several rAAV vectors that have been used in a variety of experimental settings such as prevention of neuronal death, a feature of many neurodegenerative disorders, or for gene transfer in the skeletal muscle and heart. Although rAAV vectors are extremely promising for gene therapy applications, the mechanisms underlining the high permissivity of specific tissue in vivo and the long-term persistence, remain largely unknown. The goal of this research project is to explore the molecular mechanisms governing permissivity of different organs and tissues to the AAV-mediated gene transfer. This basic research will end up with an increased knowledge of AAV vectors biology that will have positive consequences in their use in gene therapy applications.