C3 transferase Gene Therapy for CNS Axon Regeneration

 产品说明：成人中枢神经系统（CNS）的通路在损伤后无法再生，使创伤性神经损伤或退行性疾病的受害者严重残疾。改善CNS的再生能力可以改善功能恢复，生活质量，以及降低许多这些患者的整体医疗费用。然而，一个主要的障碍是CNS对轴突再生的非许可性质。对抑制轴突再生长的分子信号级联的阐明已经确定了一个关键的作用， 常见的细胞内“分子开关”- RhoA GTdR。C3转移酶是一种细菌胞外酶，通过ADP-核糖基化抑制RhoA，并且其局部应用在各种CNS损伤模型中促进轴突再生长。然而，这种递送方法限于几天的持续时间，可能不足以再生长轴突和持续的神经元存活。 为了解决这些问题，我们设计了病毒载体，以允许通过基因治疗连续递送C3。已经开发出一种可渗透细胞且可分泌的C3版本，用于更广泛、更有效的RhoA灭活。我们的目的是测试病毒载体介导的C3表达的多种不同方法，以确定在视神经损伤模型（视神经挤压（ONC））中CNS轴突再生的最有效递送和治疗窗。这些实验的成功结果将为我们的方法扩展到治疗其他神经病理学奠定基础，包括脊髓损伤，脑损伤，中风和神经退行性疾病。

 DESCRIPTION: Pathways in the adult central nervous system (CNS) are unable to regenerate after injury, leaving victims of traumatic nerve damage or degenerative disease severely disabled. Improving the regenerative capacity of the CNS may improve functional recovery, quality of life, as well as decrease overall healthcare costs for many of these patients. A major hurdle, however, is the non-permissive nature of the CNS to axon regeneration. Elucidation of the molecular signaling cascades that inhibits axon re- growth has identified the pivotal role of a common intracellular 'molecular switch' - RhoA GTPase. C3 transferase, a bacterial exoenzyme, inhibits RhoA via ADP- ribosylation and its local application promotes axon re-growth in various CNS injury models. This method of delivery is however limited to a duration of several days, likely insufficient for the regeneration of long axons and sustained neuron survival. To address these issues, we have engineered viral vectors to allow continuous delivery of C3 via gene therapy. A cell-permeable and secretable version of C3 has been developed for more widespread and effective RhoA inactivation. Our objective is to test a variety of different approaches of viral vector - mediated C3 expression to identify the most effective delivery and therapeutic window for CNS axon regeneration in a model of optic nerve injury, the optic nerve crush (ONC). The successful results of these experiments will lay the foundation for the extension of our approach to treat other neuropathology's including spinal cord injury, brain injury, and stroke and neurodegenerative diseases.