32^nd European Neurology Congress

Current treatments for brain tumours have faced major challenges including lack of tumour selectivity and the bloodbrain barrier (BBB). Development of a selective delivery system for brain tumours would play a major advance in the treatment of these tumours. For instance, successful exploitation of numerous therapeutic agents depends, essentially on the development of non-invasive nucleic acid delivery platforms. Indeed, gene therapy is promising in this disease and brain tumours were the first to be treated by clinical gene therapy but success has been limited by the inefficiency of vectors and by the BBB. We have used bacteriophage (phage), bacteria virus, to develop tumour targeted systemic vectors. Phages have a historic safety profile as they have been administered to human over many years to treat infectious diseases. Importantly, the filamentous M13 phage is able to traverse the BBB. However, phage has no strategies to deliver genes to human cells. We reported a bacteriophage vector, as hybrid genome between two single-stranded DNA of human adenoassociated virus (AAV) and filamentous M13 phage, termed AAV phage or AAVP, in which gene expression is under the control of AAV genome. We and independent groups reported efficacy of selective intravenous cancer gene therapy, with the RGD4C-AAVP displaying RGD4C ligand to target the tumour specifi c αvβ3 integrin receptor. To validate our systemic delivery platform for brain tumours, we showed the ability of the phage vector administered intravenously to home selectively to human glioblastoma (GBM), in preclinical models, through the BBB by binding the αvβ3 integrin, subsequently delivering a recombinant rAAV genome that delivers a suicide gene therapy in tumour cells, angiogenic endothelial cells and GBM-derived stem cells. Combination with a low dose of temozolomide (TMZ) enhanced gene delivery/therapy by using a tumour specific promoter from an endogenous gene associated with GBM resistance to TMZ chemotherapy. These findings provide evidence that bacteriophage is a promising delivery platform for use in targeted treatment in neuro-oncology.