Polio Replicon Gene Therapy for Damaged CNS

描述(申请人提供)：将编码生物活性分子的基因输送到中枢神经系统(CNS)的基因疗法为受损的CNS提供了新的治疗方法。由于生长中的轴突被认为遇到了大量的障碍，诱使受损的轴突从存活的神经元中再生是困难的。在鉴定对受损的中枢神经系统有治疗作用的小的生物活性蛋白方面已经取得了相当大的进展。其中许多分子统称为神经营养因子(NFs)，促进神经元存活，参与神经系统的发育、维护和对创伤的反应。除神经营养因子外，研究还发现，IL-10等细胞因子可减轻中枢神经系统损伤或创伤后的炎症反应。深刻地影响着修复的潜力。早期试图通过直接给药来提供这些生物活性分子，但由于毒性和不良副作用而遇到了失望。对于这些分子的最佳输送来说，最重要的是一种载体，它允许输送到中枢神经系统的特定细胞，并结合模仿这些蛋白质的生物表达模式的谨慎表达。最近，我们描述了一种基于脊髓灰质炎病毒(称为复制子)的新型基因递送载体，它可以在7296小时内将生物活性分子安全递送到中枢神经系统中的神经元。为了测试复制子的治疗价值，我们建立了一个脊髓损伤模型，使用对复制物敏感的小鼠。为了进一步提高复制体的治疗潜力，我们将评估复制体以及已知含有干细胞的成人脑或骨髓细胞的能力，以促进受损中枢神经系统的修复。具体目标如下：1)研究复制后外源基因在动物中枢神经系统中的表达。2)评估编码细胞因子或神经营养因子的复制体在改善急性脊髓损伤后临床预后方面的疗效。3)确定复制子在中枢神经系统刺激干细胞生长和分化的潜力。4)评价复制子对改善慢性脊髓损伤动物临床状态的作用。这些研究的结果应该会为脊髓损伤和中枢神经系统损伤引起的神经疾病提供新的治疗途径。

DESCRIPTION (provided by applicant): 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.