Potent Analgesic Conopeptides for Treatment of Chronic Spinal Cord Injury Pain

描述(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，因为传统的止痛药充其量只能起到轻微的效果，而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对康复计划的参与，导致较差的长期预后和功能恢复。我们的实验室一直在评估传统和非传统止痛药单独和联合使用在脊髓损伤疼痛的脊柱夹压迫模型中减少神经病理性疼痛症状的能力。该模型产生持续的脊髓损伤疼痛症状，并证明了成功区分临床疗效适中的药物和报道的在减少临床脊髓疼痛方面无效的药物的能力。海洋螺螺肽(螺螺肽)已成为这一适应症的特别有希望的候选药物。锥螺产生许多具有选择性离子通道阻断活性的新型多肽，已成为治疗中枢神经系统损伤和疾病新药开发的主要焦点。其中可能针对疼痛通路的有omega-conopepticMVIIA，一种具有N型钙通道阻断活性的肽(已获得FDA批准作为治疗严重疼痛的衍生物Prialt)和Conantokin-G(Conantokin-G)，一种具有NMDA拮抗剂活性的肽。我们实验室的最新发现显示，鞘内注射这些螺杆菌多肽后，疼痛反应明显改善，呈剂量依赖关系，没有明显的不良副作用，当联合使用时，具有很强的协同止痛作用。这些发现是值得注意的，因为在这个模型或临床SCI疼痛报告中，即使是其他药物组合也很难获得适度的效果。这项针对PA-10-007(疼痛研究中的机制、模型、测量和管理)的探索性/发展性R21提案的目标是：1)探索鞘内长期给药的潜力，以缓解慢性脊髓损伤疼痛；2)开发一种使用基因疗法或移植细胞提供持续椰子肽给药的方法。实现这一目标的具体目标是：1)表征神经病理性疼痛的能力和慢性椰子肽给药的有效剂量、时程和副作用；2)评估通过基因治疗或基于细胞的策略长期给药的可能性。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获取，目前正在进行脊髓损伤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，因为据报道它是安全的，并用于其他神经疾病的临床试验。如果成功，该项目将加快为脊髓损伤患者带来有效止痛治疗的进程，并在虚弱的慢性疼痛的治疗管理中提出新的高影响策略。 公共卫生相关性：据估计，高达70%的患者会出现脊髓损伤后的慢性疼痛，至少三分之一的患者认为这种疼痛非常严重，以至于成为他们参与日常活动和社会福祉的主要障碍。脊髓损伤后的神经病理性疼痛对治疗特别抵抗，其持续性会限制康复治疗的参与，并进一步降低功能恢复。因此，迫切需要找到有效的长期治疗方法来缓解慢性脊髓损伤疼痛。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的和显著选择性的自然衍生多肽(刀豆肽)缓解脊髓损伤后慢性疼痛的潜力。

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.