Targeted Motor Neuron Gene Delivery for Spasticity

描述（由申请人提供）：技术进步提供了 神经外科与神经功能恢复的新范例。的 精确的立体定位和脑深部电刺激（DBS）的双重出现， 产生了一场革命，在应用有针对性的神经调节 运动障碍、癫痫、饮食失调、强迫症 疾病和疼痛（附录C）。然而，由于DBS依赖于专注于 由于它是电流输送，因此不能具有药理学特异性。 病毒载体不是传递电流，而是改变突触， 具有分子特异性。此外，可以修饰载体向性， 产生系统特异性神经元基因递送的潜力。的 该提案中概述的实验试图开发一种能够 神经趋向性和神经调节。为了检验这些概念，我们建议 开发一种重组腺相关病毒（rAAV）， 抑制和运动神经元向性。我们选择脊髓反射弧作为 简单的哺乳动物功能系统服从神经调节。此外，本发明还提供了一种方法， 功能障碍，痉挛，提供了一个目标的研究应用 神经调节我们假设能够特异性运动的rAAV载体 神经元抑制将在以下动物模型中具有治疗功效： 痉挛除了提供一种治疗痉挛的新方法外， 这些研究将允许合理设计rAAV载体用于应用 运动神经元疾病（ALS）和立体定向神经调节。有3 目的： 1)构建能够集中突触抑制的新型载体， 2)开发用rAAV向运动神经元靶向基因递送的策略， 3)在痉挛模型中应用能够抑制突触的靶向rAAV。 申请人对行为的神经基础产生了浓厚的兴趣， 正常和病理状态。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，专注于研究基于基因的神经调节。 他对克利夫兰诊所基金会的任命将使他获得一个 功能神经外科最活跃的项目，并创建 他的工作的临床应用的机会。

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.