Gene therapy for delivery of genes encoding, biologically active molecules to the central nervous system (CNS) offers new therapeutic approaches for the damaged CNS. To entice the damaged axons from the surviving neurons to regenerate is difficult due to a large number of obstacles the growing axon is thought to encounter. There has been considerable progress in the identification of small biologically active proteins that can have therapeutic benefits to the damaged CNS. A number of these molecules, collectively called neurotrophic factors (NFs), promote neuronal survival and are involved in nervous system development, maintenance and response to trauma. In addition to NFs, studies have found that cytokines such as IL-10 reduce inflammation following injury or trauma to the CNS. Profoundly affecting the potential for repair. Early attempts at providing these biologically active molecules by direct administration though met with disappointment due to toxicity and undesirable side affects. What is essential for the optimal delivery of these molecules is a vector that allows delivery to specific cells of the CNS coupled with discreet expression that mimics the biological expression patterns of these proteins. We have recently, described a new and novel gene delivery vector based on poliovirus (called replicons) that allows safe delivery of biologically active molecules to neurons in the CNS over a 7296 hour period. To test the therapeutic value of replicons we have established a spinal cord injury, model using mice that are susceptible to replicas. To further improve the therapeutic potential of replicons, we will assess the capacity of replicas along with cells of the adult brain or bone marrow which are known to contain stem cells, to facilitate the repair of the damaged CNS. The following Specific Aims are proposed: 1) To characterize foreign gene expression in the CNS of animals following inoculation with replicas. 2) To assess the therapeutic benefits of replicas encoding cytokines or neurotrophic factors to improve clinical outcome following acute spinal cord trauma. 3) To determine the potential of replicons to stimulate stem cell growth and differentiation in the CNS. 4) To evaluate the therapeutic potential of replicons to improve the clinical condition of animals with chronic spinal cord injury. The results of these studies should provide new therapeutic avenues for spinal cord injury and neurological diseases that result from damage to the CNS.
| Jackson, Cheryl A; Messinger, Jeffery; Peduzzi, Jean D et al. (2005) Enhanced functional recovery from spinal cord injury following intrathecal or intramuscular administration of poliovirus replicons encoding IL-10. Virology 336:173-83 |
| Jackson, Cheryl A; Messinger, Jeff; Palmer, Matthew T et al. (2003) Gene expression in the muscle and central nervous system following intramuscular inoculation of encapsidated or naked poliovirus replicons. Virology 314:45-61 |
