Polio Replicon Gene Therapy for Damaged CNS

描述（由申请人提供）：用于将编码生物活性分子的基因递送至中枢神经系统（CNS）的基因疗法为受损的CNS提供了新的治疗方法。从存活的神经元中诱导受损的轴突再生是困难的，因为生长的轴突被认为会遇到大量的障碍。在鉴定对受损CNS具有治疗益处的小生物活性蛋白质方面已经取得了相当大的进展。这些分子中的一些，统称为神经营养因子（NF），促进神经元存活，并参与神经系统发育，维持和对创伤的反应。除了NF之外，研究还发现细胞因子如IL-10减少CNS损伤或创伤后的炎症。严重影响了修复的可能性。通过直接给药提供这些生物活性分子的早期尝试由于毒性和不希望的副作用而令人失望。对于这些分子的最佳递送至关重要的是允许递送至CNS的特定细胞的载体，其与模拟这些蛋白质的生物表达模式的谨慎表达偶联。我们最近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，其允许在7296小时内将生物活性分子安全递送至CNS中的神经元。为了测试复制子的治疗价值，我们使用对复制品敏感的小鼠建立了脊髓损伤模型。为了进一步提高复制子的治疗潜力，我们将评估复制子沿着已知含有干细胞的成人脑或骨髓细胞促进受损CNS修复的能力。提出了以下具体目的：1）表征重复接种后动物CNS中外源基因的表达。2)评估编码细胞因子或神经营养因子的复制品对改善急性脊髓创伤后临床结局的治疗益处。3)确定复制子刺激CNS中干细胞生长和分化的潜力。4)评估复制子改善慢性脊髓损伤动物临床状况的治疗潜力。这些研究的结果将为脊髓损伤和中枢神经系统损伤引起的神经系统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.