Spinal Neuroimmune Mechanisms Underlying IL-10 Gene Therapy for Pain Control

IL-10 疼痛控制基因疗法背后的脊髓神经免疫机制

• 批准号: 8677834
• 负责人: ERIN Damita MILLIGAN
• 金额: $ 32.14万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677834
• 关键词: American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Award; Basic Science; Biochemical; Biochemical Process; Biological Process; Cell Culture Techniques; Cell Survival; Cell physiology; Cells; Cellular Structures; Chemotaxis; Clinical; Clinical Trials; Collecting Cell; DNA; Data; Dendritic Cells; Devices; Dose; Drug Delivery Systems; Drug Formulations; Effectiveness; Encapsulated; Etiology; Exposure to; FDA approved; Gene Delivery; Gene Expression; Gene Transfer; Glycolates; Goals; Grant; Health; IL10 gene; Immune; In Vitro; Injection of therapeutic agent; Interleukin-10; Lead; Mediating; Microglia; Mitosis; Mitotic; National Institute of Drug Abuse; Neuroglia; Neuroimmunomodulation; Neurons; Non-Viral Vector; Pain; Pain management; Pathway interactions; Persistent pain; Phagocytosis; Pharmaceutical Preparations; Phenotype; Plasmid Cloning Vector; Play; Polymers; Population; Procedures; Process; Production; Proteins; Rattus; Reporter; Reporter Genes; Research; Role; Series; Signal Transduction; Signaling Protein; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord posterior horn; Spinal meninges; Staging; Syndrome; Techniques; Testing; Therapeutic; Time; Transgenes; Treatment Efficacy; Viral; Work; cell type; chronic neuropathic pain; cytokine; design; dosage; gene therapy; improved; in vivo; macrophage; novel strategies; painful neuropathy; plasmid DNA; preclinical study; prevent; release factor; research study; response; therapeutic gene; therapeutic transgene; transgene expression; uptake; vector

DESCRIPTION (provided by applicant): The present proposal is a competing renewal of a Stage II NIDA Cutting Edge Basic Research Award (CEBRA). Its aims are focused on developing a new therapy for persistent pain relief. Persistent pain (3+ months) is a common, unresolved health problem in Americans. A recent consideration in our understanding of neuropathic pain (pathological neuronal signaling in the pain pathway) includes the contribution of immune cells & glia (astrocytes, microglia, Satellite & Schwann) in pain relevant compartments such as the spinal cord dorsal horn, spinal meninges associated subarachnoid matrix, & dorsal root ganglia. Spinal cord glia mediate pathological pain via the release of well-characterized proinflammatory cytokines. The anti-inflammatory cytokine, interleukin-10 (IL-10), potently inhibits proinflammatory cytokine actions. During the current grant period, data strongly support spinal subarachnoid (intrathecal; IT) gene delivery of IL-10 prevents & reverses pathological pain in animal models. Long-duration (3+ months) pain relief is achieved upon 2 sequential IT injections of non-viral vectors, where the 2nd injection must encode IL-10 (plasmid DNA encoding IL-10; pDNA- IL-10). The first injection serves to sensitize the spinal subarachnoid compartment to the 2nd injection that creates IL-10-dependent long-duration pain relief. A robust accumulation of glia, macrophage &/or dendritic cells are components of sensitization. IL-10 protein signaling during the sensitization interval is necessary for long-duration IL-10 gene therapy. We postulate that several immune interrelated etiologies, including chemotaxis, mitosis, & phagocytosis play critical roles for sensitization & IL-10 transgene uptake. Thus, activated (chemotactic &/or mitotic) immune cells & glia could be responsible, in part, for the sensitized response to pDNA-IL-10 uptake. An FDA-approved synthetic polymer improves pDNA-IL-10 drug delivery after a single injection at reduced dosage formulations. However, further improvement is needed for clinical trials. Identifying the anatomical region, cell type and cellular activity underlying sensitization can be exploited to further improve polymer spinal IL-10 targeted gene delivery. The aims of the present proposal are straightforward: (1) To identify the cellular/biochemical responses in pain-relevant regions during sensitization; (2) To examine whether the cellular/biochemical profiles important during sensitization are also necessary during long duration gene expression and pain relief; and (3) To further improve IT gene delivery using PLGA- pDNA-IL-10 formulations that include co-release of factors important during sensitization & long-duration gene expression such that enduring pain relief can be achieved from a single injection.

描述(由申请人提供)：本提案是NIDA第二阶段尖端基础研究奖(CEBRA)的竞争性续展。它的目标是开发一种新的治疗持续性疼痛的方法。持续性疼痛(3个月以上)是美国人常见的、尚未解决的健康问题。最近我们对神经病理性疼痛(疼痛通路中的病理性神经元信号)的理解包括免疫细胞和胶质细胞(星形胶质细胞、小胶质细胞、卫星和施万恩)在疼痛相关区域的作用，如脊髓背角、脊膜相关蛛网膜下腔基质和背根神经节。脊髓胶质细胞通过释放具有良好特征的促炎细胞因子来调节病理性疼痛。抗炎细胞因子白介素10(IL-10)可以有效地抑制促炎细胞因子的作用。在当前的资助期内，数据有力地支持了脊椎蛛网膜下腔(鞘内；IT)基因输送IL-10预防和逆转动物模型中的病理性疼痛。持续时间长(3个月以上)的疼痛缓解是通过连续两次非病毒载体IT注射实现的，其中第二次注射必须编码IL-10(编码IL-10的质粒DNA；PDNA-IL-10)。第一次注射用于使脊髓蛛网膜下腔对第二次注射敏感，第二次注射产生依赖IL-10的长时间疼痛缓解。神经胶质细胞、巨噬细胞和/或树突状细胞的大量聚集是致敏的组成部分。致敏期间的IL-10蛋白信号转导对于长期的IL-10基因治疗是必要的。我们推测，包括趋化作用、有丝分裂和吞噬作用在内的几种免疫相关病因在致敏和IL-10转基因摄取中起着关键作用。因此，激活的(趋化和/或有丝分裂的)免疫细胞和胶质细胞可能部分负责对pDNA-IL-10摄取的敏化反应。FDA批准的一种合成聚合物在一次注射后以较少的剂量配方改善了PDNA-IL-10的药物输送。然而，临床试验还需要进一步改进。识别致敏作用下的解剖区域、细胞类型和细胞活性可用于进一步改善聚合物脊髓IL-10靶向基因的传递。本建议的目的很简单：(1)确定致敏过程中疼痛相关区域的细胞/生化反应；(2)研究在致敏过程中至关重要的细胞/生化谱是否也是长时间基因表达和止痛所必需的；(3)利用PLGA-PDNA-IL-10制剂进一步改善IT基因的传递，其中包括致敏过程中重要因子的共释放和长时间的基因表达，使得一次注射即可达到持久的止痛效果。

项目成果

The Central Role of Glia in Pathological Pain and the Potential of Targeting the Cannabinoid 2 Receptor for Pain Relief.

• DOI: 10.5402/2011/593894
• 发表时间: 2011-12
• 期刊: ISRN anesthesiology
• 作者: J. Wilkerson;E. Milligan

Improvement of spinal non-viral IL-10 gene delivery by D-mannose as a transgene adjuvant to control chronic neuropathic pain.

通过D-甘露糖作为转基因辅助剂来改善脊柱非病毒IL-10基因递送，以控制慢性神经性疼痛。

• DOI: 10.1186/1742-2094-11-92
• 发表时间: 2014-05-21
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Dengler EC;Alberti LA;Bowman BN;Kerwin AA;Wilkerson JL;Moezzi DR;Limanovich E;Wallace JA;Milligan ED
• 通讯作者: Milligan ED

Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia.

• DOI: 10.1213/ane.0000000000001662
• 发表时间: 2017-01
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Whitehead RA;Lam NL;Sun MS;Sanchez J;Noor S;Vanderwall AG;Petersen TR;Martin HB;Milligan ED
• 通讯作者: Milligan ED

The maternal-placental-fetal interface: Adaptations of the HPA axis and immune mediators following maternal stress and prenatal alcohol exposure.

• DOI: 10.1016/j.expneurol.2022.114121
• 发表时间: 2022-09
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Ruffaner-Hanson, Chaselyn;Noor, Shahani;Sun, Melody S.;Solomon, Elizabeth;Marquez, Lidia Enriquez;Rodriguez, Dominique E.;Allan, Andrea M.;Caldwell, Kevin K.;Bakhireva, Ludmila N.;Milligan, Erin D.
• 通讯作者: Milligan, Erin D.

Peripheral versus central mechanisms of the cannabinoid type 2 receptor agonist AM1710 in a mouse model of neuropathic pain.

• DOI: 10.1002/brb3.1850
• 发表时间: 2020-12
• 期刊: Brain and behavior
• 影响因子: 3.1
• 作者: Wilkerson JL;Alberti LB;Kerwin AA;Ledent CA;Thakur GA;Makriyannis A;Milligan ED
• 通讯作者: Milligan ED