Spinal Cord Transplants of GABAergic Precursor Cells to Treat Chronic Pain

描述（由申请人提供）：脊髓背角中抑制回路的丧失是神经损伤后持续性疼痛（神经性疼痛）的主要原因之一。 抑制的丧失不仅导致自发性疼痛的发展，而且导致作为这些临床病症特征的异常性疼痛和痛觉过敏的基础的过度兴奋。神经损伤引起的神经性疼痛的药理学管理是针对增强抑制控制，但不幸的是，并非所有患者都对这种疗法有反应。此外，由于治疗通常涉及全身性药物施用而产生的不良副作用通常限制了有效剂量的使用。我们建议开发一种新的治疗方法（前体抑制神经元移植），旨在恢复脊髓中的抑制控制。治疗方案不同于针对症状管理的传统药理学疗法;移植以替代缺失的神经元间控制是一种改善疾病的方法。事实上，胚胎前体细胞的移植已经导致了各种神经退行性疾病的功能改善，但对于潜在的治疗机制以及移植细胞和宿主组织之间存在的连接程度仍然知之甚少。我们建议移植来自小鼠胚胎内侧神经节隆起（MGE）的细胞。在具体目标1中，我们将继续分析移植参与的回路，并将使用电生理学来评估抑制性控制的程度。 从移植中。在具体目标2中，我们将评估移植物缓解 由周围神经损伤产生的持续性疼痛，包括由化疗剂产生的疼痛。使用选择性拮抗剂来对抗移植的影响，我们将确定GABA是否确实是恢复的主要贡献者。最后，在具体目标3中，我们将使用一种新的化学遗传方法来实现对移植物活性的体内时空控制。这些研究将确定MGE衍生的细胞具有基于细胞的治疗的基本特性，特别是当抑制控制的丧失是临床病症的主要贡献者时。这一奋进的成功将为人类持续性疼痛的细胞移植的最终研究建立必要的概念证明。 公共卫生相关性：周围神经损伤引起的神经病理性疼痛是一个主要的临床问题，涉及改变脊髓的疼痛信息处理。在不同的小鼠神经病理性疼痛模型中，我们建议评估将胚胎前体神经细胞移植到成年脊髓中的益处。我们将检验移植的 细胞整合到宿主组织中，呈现抑制特性并减少神经损伤的病理生理学（产生疼痛）后果。

DESCRIPTION (provided by applicant): Loss of inhibitory circuits in the spinal cord dorsal horn is one of the major contributors to persistent pain following nerve injury (neuropathic pain). The loss of inhibition contributes not only to the development of spontaneous pain, but also to the hyperexcitability that underlies the allodynia and hyperalgesia that are characteristic of thes clinical conditions. Pharmacological management of nerve injury-induced neuropathic pain is directed at enhancing inhibitory controls, but unfortunately, not all patients are responsive to such therapies. Furthermore, adverse side effects, which arise because treatments typically involve systemic drug administration, often limit the use of effective doses. We propose to develop a novel therapeutic approach (transplantation of precursor inhibitory neurons) that is designed to restore the inhibitory controls in the spinal cord. The treatment regime differs from traditional pharmacological therapies that are directed at symptom management; transplantation to replace missing interneuronal control is a disease modifying approach. Transplantation of embryonic precursor cells has, in fact, resulted in functional improvement in various neurodegenerative diseases, but still very little is known about the underlying therapeutic mechanisms and the extent to which connectivity exists between grafted cells and host tissue. We propose to transplant cells derived from the mouse embryonic medial ganglionic eminence (MGE). In Specific Aim 1, we will continue our analysis of the circuits in which the transplants participate and will use electrophysiology to assess the extent to which inhibitory controls derive from the transplants. In Specific Aim 2, we will assess the ability of the transplants to alleviate the persistent pain produced by peripheral nerve injury, including those produced by chemotherapeutic agents. Using selective antagonists to counter the effects of the transplants, we will determine whether GABA is indeed the major contributor to recovery. Finally, in Specific Aim 3, we will use a novel chemical-genetic approach to achieve in vivo spatio-temporal control of the activity of the transplants. These studies will establish that MGE-derived cells have the essential properties for a cell-based therapy, particularly when loss of inhibitory control is a major contributor to the clinical condition. Success in this endeavor will establish the proof of concept necessary for eventual studies of cell transplantation for persistent pain in humans. PUBLIC HEALTH RELEVANCE: Peripheral nerve-injury induced neuropathic pain is a major clinical problem involving altered spinal cord processing of pain message. In different models of neuropathic pain in the mouse, we propose to assess the benefits of transplanting embryonic precursor nerve cells into the adult spinal cord. We will test the hypothesis that the transplanted cells integrate into host tissue, assume inhibitory properties and reduce the pathophysiological (pain-producing) consequences of the nerve injury.