Pain control via spinal interleukin-10 gene therapy

通过脊髓白细胞介素 10 基因治疗控制疼痛

基本信息

批准号：
7252604
负责人：
ERIN Damita MILLIGAN
金额：
$ 6.92万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-20 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7252604
关键词：
Acute Adverse effects Affect Animals Anti-Inflammatory Agents Anti-inflammatory Astrocytes Behavior Behavioral Blood - brain barrier anatomy Brain Cell Wall Cellular Immunity Cerebrospinal Fluid Chronic Clinical Code Confocal Microscopy DNA Data Development Diabetic Neuropathies Dose Effectiveness Endotoxins Exhibits Fever Food Gene Delivery Gene Expression Genes Green Fluorescent Proteins Human Hyperalgesia IL10 gene Immune Immune response Immune system Infection Inflammation Injection of therapeutic agent Interleukin-1 Interleukin-10 Interleukin-6 Location Maintenance Malignant Bone Neoplasm Measures Mediating Messenger RNA Microglia Modeling National Institute of Drug Abuse Neurons Neuropathy Numbers Outcome Pain Pain management Peripheral Plasmids Polyethylene Glycols Prevention Procedures Production Proteins Protocols documentation Radiculopathy Rattus Regulation Reporter Genes Resistance Route Serotyping Serum Spinal Spinal Cord Spinal Ganglia Testing Therapeutic Effect Time Tissues Transgenes Tumor Necrosis Factor-alpha Tumor Necrosis Factors Upper arm Water consumption adeno-associated viral vector base cell type chronic pain clinically relevant cytokine day design gene therapy human TNF protein interest man painful neuropathy prevent programs promoter receptor red fluorescent protein response sciatic nerve success transgene expression uptake vector vector-induced

项目摘要

DESCRIPTION (provided by applicant): The present proposal is an extension of an ongoing 2-yr R21 (Watkins, P.I.) under the NIDA CEBRA program. Its aims are focused on developing a new therapy for pain. Controlling chronic pain in humans is a major unresolved problem. Recent data strongly suggest that spinal cord gila (astrocytes & microglia) are critically involved in the creation & maintenance of diverse enhanced pain states. Spinal cord gila create enhanced pain via the release of proinflammatory cytokines (PlCs): tumor necrosis factor (TNF), interleukin-1 (IL1) & interleukin-6 (IL6). Recognition of the key importance of spinal cord gila & glial PICs in pathological pain opens new avenues for pain control. There are various pharmacological means available to control glial dysregulation of pain. Interleukin-10 (IL10) is very promising from a clinical point of view.' IL10 is an anti-inflammatory cytokine, which acts as an endogenous suppressor of proinflammatory cytokine production & activity. IL10 is an excellent candidate for preventing & reversing PIC-driven pathological pain states. However, two practical problems need to be overcome. First, control of chronic pain requires chronic delivery of IL10. Second, IL10 cannot cross the blood-brain barrier, thus negating systemic administration. To resolve these issues, we are exploring the feasibility of prolonged spinal release of Ll10 induced by gene therapy. Here, vectors encoding IL10 are injected into the cerebrospinal fluid surrounding the spinal cord (intrathecal; IT), so as to mimic a clinically relevant route of delivery. Our preliminary data provide strong support that spinal gene therapy with IL10 will prevent & reverse enhanced pain states. The aims of the present proposal are straightforward: (1) To identify the optimal vectors from a limited number of candidates, in terms of their effectiveness in transcribing the gene of interest & reversing clinically relevant pain models; (2) To examine the mechanisms by which these optimal IL10-inducing vectors exert their effects in spinal cord; and (3) to examine potential short-comings of this approach. Together, these studies will test the premise that gene therapy with IL10 is worthy of clinical development for controlling diverse pathological pain states. This approach to pain control represents a dramatic departure from all other available therapies.

描述（由申请人提供）：本提案是 NIDA CEBRA 计划下正在进行的 2 年 R21（P.I. 沃特金斯）的延伸。其目标是开发一种新的疼痛疗法。控制人类慢性疼痛是一个尚未解决的重大问题。最近的数据强烈表明，脊髓胶质细胞（星形胶质细胞和小胶质细胞）在多种增强疼痛状态的产生和维持中发挥着重要作用。脊髓吉拉病毒通过释放促炎细胞因子 (PlC) 来增强疼痛：肿瘤坏死因子 (TNF)、白细胞介素 1 (IL1) 和白细胞介素 6 (IL6)。认识到脊髓胶质细胞和神经胶质 PIC 在病理性疼痛中的关键重要性，为疼痛控制开辟了新途径。有多种药理学方法可用于控制神经胶质细胞失调的疼痛。从临床角度来看，白介素 10 (IL10) 非常有前景。 IL10 是一种抗炎细胞因子，可作为促炎细胞因子产生和活性的内源性抑制剂。 IL10 是预防和逆转 PIC 驱动的病理性疼痛状态的绝佳候选者。然而，有两个实际问题需要克服。首先，控制慢性疼痛需要长期输送 IL10。其次，IL10不能穿过血脑屏障，因此无法全身给药。为了解决这些问题，我们正在探索基因治疗诱导Ll10延长脊髓释放的可行性。在这里，编码 IL10 的载体被注射到脊髓周围的脑脊液中（鞘内；IT），以模拟临床相关的递送途径。我们的初步数据有力地支持了 IL10 脊髓基因治疗将预防和逆转增强的疼痛状态。本提案的目标很简单：（1）从有限数量的候选者中识别最佳载体，以了解它们在转录感兴趣基因和逆转临床相关疼痛模型方面的有效性； (2) 研究这些最佳IL10诱导载体在脊髓中发挥作用的机制； (3) 检查这种方法的潜在缺点。这些研究将共同检验这样一个前提：IL10 基因疗法值得临床开发以控制不同的病理疼痛状态。这种疼痛控制方法与所有其他可用疗法截然不同。