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: 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
• 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

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项目下正在进行的2年R21（沃特金斯，P.I.）的延伸。它的目标是开发一种治疗疼痛的新疗法。