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

• 批准号: 6807153
• 负责人: ERIN Damita MILLIGAN
• 金额: $ 38.67万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807153
• 关键词: Adenoviridae; RNA virus; analgesia; arthritis; behavior test; bone neoplasms; cerebrospinal fluid; confocal scanning microscopy; cytokine receptors; diabetic neuropathy; enzyme linked immunosorbent assay; gene therapy; hyperalgesia; immunoregulation; interleukin 10; laboratory rat; plasmids; spinal cord; therapy design /development; transfection /expression vector

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）：本提案是正在进行的2年R21（Watkins，P.I.）在NIDA CEBRA计划下。其目标是开发一种新的疼痛疗法。 控制人类的慢性疼痛是一个尚未解决的主要问题。最近的数据有力地表明，脊髓胶质细胞（星形胶质细胞和小胶质细胞）是至关重要的参与创造和维持不同的增强疼痛状态。脊髓神经胶质瘤通过释放促炎细胞因子（PLC）产生增强的疼痛：肿瘤坏死因子（TNF）、白细胞介素-1（IL 1）和白细胞介素-6（IL 6）。认识到脊髓神经胶质细胞在病理性疼痛中的重要性，为疼痛控制开辟了新的途径。 有多种药理学手段可用于控制神经胶质对疼痛的调节异常。白细胞介素-10（IL-10）从临床角度来看非常有前途。IL 10是一种抗炎细胞因子，其充当促炎细胞因子产生和活性的内源性抑制剂。IL 10是预防和逆转PIC驱动的病理性疼痛状态的优秀候选者。 然而，有两个实际问题需要克服。首先，慢性疼痛的控制需要IL 10的慢性递送。其次，IL 10不能穿过血脑屏障，因此否定了全身给药。为了解决这些问题，我们正在探索通过基因治疗诱导的Ll 10的延长脊髓释放的可行性。在此，将编码IL 10的载体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。我们的初步数据提供了强有力的支持，即IL 10的脊柱基因治疗将预防和逆转增强的疼痛状态。 本提案的目的很简单：（1）从有限数量的候选者中鉴定最佳载体，就其在转录感兴趣的基因和逆转临床相关疼痛模型中的有效性而言;（2）检查这些最佳IL 10诱导载体在脊髓中发挥其作用的机制;以及（3）检查这种方法的潜在缺点。总之，这些研究将测试IL 10基因疗法值得临床开发以控制不同病理性疼痛状态的前提。这种控制疼痛的方法与所有其他可用的治疗方法截然不同。