Targeted Motor Neuron Gene Delivery for Spasticity

描述(由申请人提供)：技术进步提供了 恢复神经功能的新范例的神经外科。这个 精确的立体定向和脑深部刺激(DBS)的双重出现 产生了一场革命，应用于靶向神经调节的应用 运动障碍、癫痫、进食障碍、强迫症 疾病和疼痛(附录C)。尽管如此，因为星展银行依赖于 输送电流时，它不具备药理特异性。 病毒载体可以改变突触，而不是传递电流 具有分子特异性的功能。此外，可以修改向量取向， 为系统特定的神经元基因传递创造了可能性。这个 这项提案中概述的实验试图开发一种能够 既有神经取向也有神经调节。为了测试这些概念，我们建议 一种可突触的重组腺相关病毒的研制 抑制和运动神经元趋向性。我们选择了脊椎反射弧线作为 简单的哺乳动物功能系统，服从神经调节。此外, 痉挛这一功能性障碍为临床应用研究提供了一个靶点 神经调节。我们假设有一种rAAV载体能够特异性运动 神经元抑制将在动物模型中起到治疗作用 痉挛。除了提供一种治疗痉挛的新方法外，来自 这些研究为合理设计应用重组腺相关病毒载体(S)奠定了基础 运动神经元病(ALS)和立体定向神经调节。有3个 目标： 1)构建能够聚焦突触抑制的新型载体， 2)开发rAAV向运动神经元靶向基因传递的策略， 3)在痉挛模型中应用具有突触抑制作用的靶向rAAV。 申请者对行为的神经基础产生了浓厚的兴趣 无论是正常状态还是病理状态。他早期接受的简单系统训练 神经生理学，以及后来的生物化学和分子生物学培训 为他的职业生涯做好了准备，从事专注于基因神经调节的研究。 他在克利夫兰诊所基金会的任命将使他有机会接触到 在功能神经外科最活跃的项目中，并创建 为他的工作提供临床应用的机会。

DESCRIPTION (provided by applicant): Technological advancements have provided neurosurgery with new paradigms for the restoration of neural function. The dual emergence of accurate stereotaxis and deep brain stimulation (DBS) have generated a revolution in the application of targeted neuromodulation applied to movement disorders, epilepsy, eating disorders, obsessive compulsive disease, and pain (Appendix C). Nonetheless, because DBS depends on the focused delivery of electric current, it is incapable of pharmacological specificity. Rather than delivering electric current, viral vectors can alter synaptic function with molecular specificity. Further, vector tropism can be modified, creating the potential for system specific neuronal gene delivery. The experiments outlined in this proposal attempt to develop a vector capable of both neural tropism and neuromodulation. To test these concepts, we propose to develop a recombinant adeno-associated virus (rAAV) capable of synaptic inhibition and motor neuron tropism. We have chosen the spinal reflex arc as a simple mammalian functional system amenable to neuromodulation. In addition, the functional disorder, spasticity, provides a target for the study of applied neuromodulation. We hypothesize that an rAAV vector capable of specific motor neuron inhibition will have therapeutic efficacy in animal models of spasticity. In addition to providing a novel approach to spasticity, data from these studies will permit the rational design of rAAV vector(s) for application to motor neuron disease (ALS) and stereotactic neuromodulation. There are 3 Aims: 1) Construct novel vectors capable of focused synaptic inhibition, 2) develop strategies for targeted gene delivery to motor neurons with rAAV, 3) apply targeted rAAV capable of synaptic inhibition in models of spasticity. The applicant has developed a focused interest in the neural basis for behavior in both normal and pathological states. His early training in simple systems neurophysiology, and later training in biochemistry and molecular biology have prepared him for a career in the study of focused gene-based neuromodulation. His appointment to the Cleveland Clinic Foundation will give him access to one of the most active programs in Functional Neurosurgery, and create opportunities for clinical application of his work.