Ion channel targets for treatment of neuropathic pain

描述(申请人提供)：ALGOS治疗公司是一家生物制药公司，该公司寻求为早期药物发现研究提供资金，该研究旨在验证两个专有离子通道作为治疗神经性疼痛的分子靶标的有效性。神经病理性疼痛是由神经损伤引起的，似乎涉及感觉神经元过度的电活动和外周感受野的不适当炎症。患有糖尿病、癌症、关节炎、多发性硬化症和病毒感染(疱疹)的患者有患神经性疼痛的风险。对于这种慢性疼痛，现在几乎没有有效的治疗方法。这项第一阶段的SBIR提案包含了一项研究，将确定这些靶点在全身和疼痛路径中的位置。这将通过测量编码我们的靶标的mRNA以及使用免疫细胞化学和Western印迹技术检测靶标蛋白来完成。这些靶点将使用神经病理性疼痛的动物模型进一步验证。鞘内注射反义寡核苷酸可阻断靶点的正常功能。这种治疗将减少疼痛通路中表达的靶点的数量，从而降低它们的正常功能。采用痛觉超敏和热痛敏的行为学指标来评价反义治疗的镇痛效果。初步数据表明，我们的目标参与了疼痛信号传递，并证明了我们的技术能力以及我们战略的可行性。这个第一阶段项目的目标是确定我们的两个目标中哪一个代表了最具生物学意义的痛觉阻塞点。第二阶段的提案将涉及后期药物发现研究，如化验开发、寻找铅和优化铅。该项目的直接目标是生产一种针对我们最具吸引力的分子靶点的化合物，该化合物可用于人体临床测试。我们工作的长期目标是开发一种有效和安全的神经性疼痛治疗方法。

DESCRIPTION (provided by applicant): Algos Therapeutics, Inc., a biopharmaceutical company, seeks funding for early drug discovery research designed to validate two proprietary ion channels as molecular targets for treatment of neuropathic pain. Neuropathic pain is initiated by nerve damage and appears to involve excessive electrical activity in sensory neurons and inappropriate inflammation of peripheral receptive fields. Patients with diabetes, cancer, arthritis, multiple sclerosis, and viral infections (herpes) are at risk for neuropathic pain. Few effective therapies for this type of chronic pain are now available. This Phase I SBIR proposal encompasses research that will determine where these targets are located both throughout the body and specifically in pain pathways. This will be done through measurment of mRNA encoding our targets and detection of the target proteins using immunocytochemistry and Western blot technology. The targets will be further validated using animal models of neuropathic pain. The normal function of the targets will be blocked by administration of antisense oligonucleotides to the intrathecal space. This treatment will reduce the amount of the targets expressed in the pain pathways and thereby reduce their normal function. Behavioral measures of allodynia and thermal hyperalgesia will be used to evaluate the analgesia generated by antisense treatment. Preliminary data suggests that our targets are involved in pain signaling and demonstrates our technical capabilities as well as the feasibility of our strategy. The goal of this Phase I project is to determine which of our two targets represents the most biologically important choke point of pain perception. The Phase II proposal will involve later stage drug discovery research such as assay development, lead seeking, and lead optimization. The immediate goal of this project is to produce a compound directed at our most attractive molecular target that is ready for human clinical testing. The long-term goal of our work is to develop an effective and safe treatment for neuropathic pain.