C3 transferase Gene Therapy for CNS Axon Regeneration

用于中枢神经系统轴突再生的 C3 转移酶基因治疗

基本信息

批准号：
8873702
负责人：
ROBERT E GROSS
金额：
$ 7.8万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8873702
关键词：
ADP ribosylation Actins Address Adult Amino Acids Axon Biochemical Brain Injuries Cell division Cell physiology Cells Chondroitin Sulfate Proteoglycan Clinical Treatment Clinical Trials Closed head injuries Crush Injury Cues Cytoskeleton Degenerative Disorder Dependovirus Disabled Persons Doxycycline Engineering Family Fiber Foundations Glaucoma Growth Growth Cones Guanosine Triphosphate Phosphohydrolases Health Health Care Costs Injection of therapeutic agent Injury Lead Left Length Lentivirus Vector Mediating Methods Microtubules Modeling Modification Molecular Myelin Myelin Associated Glycoprotein Natural regeneration Nature Nerve Nerve Crush Nerve Regeneration Neuraxis Neurodegenerative Disorders Neurons Neuropathy Optic Nerve Optic Nerve Injuries Pathway interactions Patients Peripheral Nervous System Diseases Permeability Physiologic pulse Play Primary Lateral Sclerosis Quality of life Rattus Recovery of Function Regulation Role Semaphorins Signal Transduction Source Spinal cord injury Stem cells Stress Fibers Stroke Testing Tetanus Helper Peptide Therapeutic Time Toxic effect Transferase Transferase Gene Viral Vector autocrine axon growth axon regeneration cell motility central nervous system injury exoenzyme extracellular gene therapy improved in vivo inhibitor/antagonist injured nervous system disorder neuropathology novel paracrine prevent public health relevance regenerative research study response rho rho GTP-Binding Proteins transgene expression vector

项目摘要

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.

描述：成人中枢神经系统（CNS）的途径在受伤后无法再生，留下了神经损害或退行性疾病的惊喜。提高中枢神经系统的再生能力可以改善功能恢复，生活质量以及降低许多患者的总体医疗费用。然而，一个主要的障碍是中枢神经系统到轴突再生的非允许性质。阐明抑制轴突重长的分子信号传导级联反应已经确定了A的关键作用常见的细胞内“分子开关” -RHOA GTPase。 C3转移是一种细菌外酶，通过ADP-核糖基化抑制RhoA及其局部应用促进了各种CNS损伤模型中的轴突重长。但是，这种传递方法仅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，我们已经设计了病毒载体，以通过基因治疗连续递送C3。已经开发了一种可渗透细胞和可分泌的C3版本，以更大且有效的RhoA失活。我们的目的是测试病毒载体的各种不同方法 - 介导的C3表达，以确定视神经损伤模型，视神经挤压（ONC）中CNS轴突再生的最有效的递送和治疗窗口。这些实验的成功结果将为扩展我们的其他神经病理学方法的方法奠定基础，包括脊髓损伤，脑损伤，中风和神经退行性疾病。