Treatment for human hepatoblastoma based on recombinant adeno-associated virus vectors

Human hepatoblastoma (HB) is the most common pediatric liver cancer in the U.S.A. More than 30 percent of patients die after a 10-year period. In addition, the existing therapies are very costly. For example, liver transplantation is estimated to cost approximately $150,000 to $200,000 per patient. Moreover, the shortage of donor livers for patients awaiting transplant and graft rejection post-transplantation significantly limit the widespread usage of this method. Thus, alternative therapies are still warranted. The main aim of this proposal is to develop novel recombinant adeno-associated virus (rAAV) vectors for the selective and highly efficient targeting of human HB tumors. rAAV vectors are currently in use in a number of gene therapy clinical trials. In previous studies, we have shown that recombinant adeno-associated virus serotype 3 (rAAV3) vectors efficiently and selectively infect HB cell lines both in vitro and in vivo. In clinic, it is important to target as many malignant cells as possible. To this end, we plan to modify both the viral capsid and viral genome to further enhance the infectivity of rAAV3 vectors in HB cells. Secondly, the capsid- and genome-optimized rAAV3 vectors containing therapeutic genes will be tested for the potential gene therapy of human HB tumors in murine models in vivo. The proposed studies will lead to a new method to cure pediatric liver cancer patients. The knowledge gained from these studies will be applicable in further application of rAAV vectors for their potential use in inducing reduction of human liver tumors, including HB.