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: 6556417
• 负责人: LINDA WATKINS
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556417
• 关键词: Adenoviridae; antiinflammatory agents; behavior test; cerebrospinal fluid; chemoprevention; complementary DNA; cytokine receptors; dorsal horn; gene delivery system; gene therapy; genetic manipulation; heat stimulus; hyperalgesia; immunotherapy; interleukin 10; laboratory rat; nerve injury; pain; pain threshold; somesthetic sensory cortex; spinal cord; transfection /expression vector

DESCRIPTION: (provided by applicant): Human pathological pain is a major unresolved problem. Recent data strongly support the argument that spinal cord glia (astrocytes and microglia) are critically involved in the creation and maintenance of diverse pathological pain states. Spinal cord glia create exaggerated pain states via the release of proinflammatory cytokines (PICs). Recognition of the key importance of spinal cord glia and glial PICs in pathological pain opens new avenues for pain control. There are various treatments available to control glial activation involved in enhanced pain. Interleukin-10 (IL10) is the most promising from a clinical point of view. IL10 is an excellent candidate for preventing and 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 have explored the feasibility of using prolonged spinal release of IL10 induced by gene therapy. Here, adenoviral vectors encoding IL10 are injected into the cerebrospinal fluid surrounding the spinal cord. Our preliminary data provide strong support for the possibility that spinal gene therapy with IL10 will prevent and reverse pathological pain. The aims of the present proposal are three-fold: (1) To determine the breadth of clinically relevant exaggerated pain states that can be prevented and/or reversed by gene therapy-induced IL10 in spinal CSF; (2) To construct a "gutless" adenoviral vector of IL10 which allows virally infected cells to avoid detection and destruction by the immune system; and (3) To characterize the patterns of IL10 release, characterize viral spread and clarity whether peripheral immune functions are impacted by this procedure. Together these studies will test the premise that intrathecal IL10 delivery via gene therapy 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）：人类病理性疼痛是一个尚未解决的重大问题。 最近的数据有力地支持了这样的论点：脊髓神经胶质细胞（星形胶质细胞和小胶质细胞）在多种病理疼痛状态的产生和维持中发挥着重要作用。 脊髓神经胶质细胞通过释放促炎细胞因子（PIC）产生夸张的疼痛状态。 认识到脊髓神经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。 有多种治疗方法可用于控制与疼痛加剧有关的神经胶质激活。 从临床角度来看，白细胞介素-10 (IL10) 是最有前途的。 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，我们探索了通过基因治疗诱导IL10延长脊髓释放的可行性。 在这里，编码 IL10 的腺病毒载体被注射到脊髓周围的脑脊液中。 我们的初步数据为使用 IL10 的脊髓基因治疗预防和逆转病理性疼痛的可能性提供了强有力的支持。 本提案的目标有三个：(1) 确定可通过基因治疗诱导脊髓 CSF 中的 IL10 来预防和/或逆转的临床相关夸大疼痛状态的范围； （2）构建IL10的“无肠”腺病毒载体，使病毒感染的细胞能够避免被免疫系统检测和破坏； (3) 表征 IL10 释放的模式、病毒传播的特征并明确外周免疫功能是否受到此过程的影响。 这些研究将共同​​检验这样一个前提：通过基因疗法进行鞘内 IL10 递送是否值得进行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。