The aim of this project is to elucidate the mechanism of cell type-specific viral translation in the central nervous system (CNS). A cis-acting genetic element located within the 5' non-translated region of picornaviruses, the internal ribosomal entry site (IRES), was found to confer specificity for cells of neuronal origin. We have developed a novel approach to treat malignant tumors of the CNS based on the principles of IRES-mediated cell type-specific translation. This strategy uses picornaviruses engineered to contain IRES elements with cell type-specific deficits in neuronal cells. These chimeric viruses exhibit excellent growth and lytic potential in cancerous cells derived from malignant brain tumors. Pre-clinical studies in non-human primates demonstrated neuronal IRES repression to render these agents safe to be used in patients. We plan to identify the molecular mechanisms of cell type-specific IRES function by mapping the genetic loci important for tissue specificity. Furthermore, the identification of eukaryotic trans-acting factors in permissive tumor cells or resistant neurons is expected to shed light on selective IRES activity in neoplastic cells. We will attempt to determine the stage of neuronal differentiation that correlates with neuronal IRES repression. Unraveling of the molecular mechanism of cell type-specific IRES function may lead to the development of novel gene expression systems with exclusive targeting to cancer cells in the CNS. Malignant tumors of the CNS are resistant to all currently available treatment modalities. Conditional replication mediated by IRES selectivity of recombinant oncolytic picornaviruses is the first example of tumor targeting at the level of translational control. This principle has shown great promise in pre-clinical studies in experimental animals and in primary explant cultures of human CNS tumors.
