Potent Analgesic Conopeptides for Treatment of Chronic Spinal Cord Injury Pain

描述（由申请人提供）：脊髓损伤（SCI）后的慢性神经性疼痛是一个特别具有挑战性的临床目标，因为传统的镇痛药物充其量只能勉强有效，并且由于所需的高剂量而充满了不良副作用。除了直接干扰这些患者的生活质量外，未经治疗的疼痛的存在可能会限制参与康复计划，导致长期预后较差和功能恢复减少。我们的实验室一直在评估传统和非传统镇痛药单独和组合，以减少脊髓夹压迫模型SCI疼痛的神经性疼痛症状的能力。该模型产生持续的SCI疼痛症状，并证明了成功区分具有中等临床疗效的药理学药物与那些报道在减轻临床SCI疼痛方面无效的药物的能力。海洋锥螺肽（conopeptides）已成为特别有前途的候选人，这一迹象。锥螺产生许多具有选择性离子通道阻断活性的新型肽，并且已经成为治疗CNS损伤和疾病的新药开发的主要焦点。在那些潜在靶向疼痛途径中有ω-芋螺肽MVIIA，一种具有N型Ca 2+通道阻断活性的肽（其已获得FDA批准作为治疗严重疼痛的衍生物Prialt）和芋螺素-G（conG），一种具有NMDA拮抗剂活性的肽。我们实验室的最新研究结果显示，鞘内推注这些锥肽后疼痛反应得到了强有力的剂量依赖性改善，没有明显的不良副作用，并且当组合使用时具有高度有效的协同疼痛减轻作用。鉴于在该模型或临床SCI疼痛报告中难以获得其他药物组合的甚至适度的效果，这些发现是显著的。本探索性/开发性R21提案响应PA-10-007（疼痛研究中的机制、模型、测量和管理）的目标是：1）探索长期鞘内递送芋螺肽组合以缓解慢性SCI疼痛的潜力; 2）开发一种使用基因治疗或移植细胞提供持续芋螺肽递送的方法。实现这一目标的具体目的是1）表征慢性芋螺肽给药的神经性疼痛减轻能力和有效剂量、时间过程和副作用; 2）评估通过基因治疗或基于细胞的策略长期递送芋螺肽的潜力。最初的研究将集中在成人骨髓干细胞上，这种干细胞可以自体来源，目前正在开发用于SCI和其他适应症的临床试验。腺相关病毒（AAV）介导的递送也将在这些初步研究中探索，因为它报告的安全性和在其他神经系统疾病的临床试验中的使用。如果成功，该项目将加速为脊髓损伤患者提供有效镇痛治疗的过程，并在慢性疼痛的治疗管理中推进新的高影响力策略。 公共卫生相关性：据估计，脊髓损伤后的慢性疼痛发生在高达70%的患者中，至少有三分之一的患者认为疼痛非常严重，这是他们参与日常活动和社会福祉的主要障碍。SCI后的神经性疼痛对治疗特别有抵抗力，其持续存在会限制参与康复治疗并进一步减少功能恢复。因此，迫切需要确定有效的长期治疗方法来缓解慢性SCI疼痛。拟议的研究将评估通过基因治疗或细胞移植方法长期提供的新型和显着选择性天然衍生肽（conopeptides）的潜力，以改善脊髓损伤后的慢性疼痛。

DESCRIPTION (provided by applicant): Chronic neuropathic pain following spinal cord injury (SCI) is a particularly challenging clinical target, as traditional analgesic drugs are only marginally effective at best, and fraught with untoward side effects owing to the high doses required. In addition to direct interference in the quality of life of these patients, the presence of untreated pain can limit participation in rehabilitation programs, resulting in poorer long-term prognosis and reduced functional recovery. Our laboratory has been evaluating traditional and non-traditional analgesics alone and in combinations for their ability to reduce neuropathic pain symptoms in a spinal clip compression model for SCI pain. This model produces persistent SCI pain symptoms, and demonstrates the ability to successfully distinguish pharmacologic agents with modest clinical efficacy from those reported to be ineffective in reducing clinical SCI pain. Marine cone snail peptides (conopeptides) have emerged as particularly promising candidates for this indication. Cone snails produce a number of novel peptides with selective ion channel blocking activity, and have become a major focus for new drug development in the treatment of CNS injury and disease. Among those potentially targeting pain pathways are the omega- conopeptide MVIIA, a peptide with N-type Ca2+ channel blocking activity (which has reached FDA approval as derivative Prialt in the treatment of severe pain) and conantokin-G (conG), a peptide with NMDA antagonist activity. Recent findings in our lab showed robust dose-dependent amelioration of pain responses following bolus intrathecal injection of these conopeptides, without apparent untoward side effects, and a highly potent synergistic pain reduction when used together in combination. These findings are remarkable in light of the difficulty in obtaining even modest effects of other drug combinations in this model or in clinical SCI pain reports. The goal of this exploratory/developmental R21 proposal in response to PA-10-007 (Mechanisms, models, measurement, & management in pain research) is to 1) explore the potential for long-term intrathecal delivery of conopeptide combinations to alleviate chronic SCI pain, and 2) to develop a means for providing sustained conopeptide delivery using gene therapy or transplanted cells. Specific aims to accomplish this are 1) To characterize neuropathic pain-reducing ability and effective dosing, time-course, and side effects of chronic conopeptide administration; 2) To evaluate the potential for long-term delivery of conopeptides via gene therapy or cell-based strategies. Initial studies will focus on adult bone marrow stem cells, which can be autologously derived and are currently being developed in clinical trials for SCI and other indications. Adeno- associated virus (AAV)-mediated delivery will also be explored in these initial studies, owing to its reported safety and use in clinical trials for other neurological disorders. If successful, this project should accelerate the process of bringing effective analgesic therapies to spinal cord injured patients, and advance novel high-impact strategies in the therapeutic management of debilitating chronic pain. PUBLIC HEALTH RELEVANCE: Chronic pain following spinal cord injury is estimated to occur in up to 70% of patients, with at least one-third rating it as so severe that it is their primary impediment to participation in daily activities and social well-being. Neuropathic pain following SCI is particularly resistant to treatment, and its persistence can limit participation in rehabilitation therapies and further reduce functional recovery. Thus there is a critical need for identifying effective long-term therapies for alleviating chronic SCI pain. The proposed studies will evaluate the potential for novel and remarkably selective naturally-derived peptides (conopeptides), delivered on a long-term basis via gene therapy or cell transplantation approaches, to ameliorate chronic pain following spinal cord injury.