Chemokine-receptor profiling for painful diabetic neuropathy in biological samples from human clinical trials

项目总结/摘要 慢性疼痛是一个主要的医疗保健负担，每年的经济成本高达6350亿美元， 根据约翰霍普金斯在《疼痛杂志》上发表的一项研究， 疼痛是一种高度异质性的疾病，包括神经性、伤害性和炎症性成分， 并且患者对当前可用药物的反应差异很大。 一种非常有前途的针对各种形式疼痛的方法是通过拮抗神经系统中的关键参与者， 炎症具体来说，趋化因子受体系统，一个复杂的网络，超过20种不同的受体和 超过80种配体，是神经炎症过程的组成部分，制药业一直非常活跃 开发针对网络中单个受体的化合物。然而，生物学的复杂性， 趋化因子受体系统的配体混杂和受体冗余已经阻碍了成功的临床应用。 化合物的开发和许多药物已经退出疼痛治疗领域。 成功靶向该网络的一个主要限制是对该网络的分子和功能的充分理解。 趋化因子网络的细胞动力学，以及特定受体在慢性疼痛条件下的变化。在这 在这项研究中，我们的目标是利用人类临床样本确定趋化因子受体的基因表达 在评估受体拮抗剂的临床试验中收集。此外，我们将利用这种理解， 结合临床试验的患者疗效数据，继续开发我们的先导化合物， 一种在疼痛方面显示出统计学显著临床信号的药物。这项研究的结果将使患者 分层和有效的临床试验设计，包括具有适当遗传和表型的患者 因此显著增加了达到疼痛减轻的主要终点的可能性。 诊所

Project Summary/Abstract Chronic pain is a major healthcare burden, representing economic costs of up to $635B per year, more than cancer, diabetes, and heart disease, according to a Johns Hopkins study published in the Journal of Pain. Pain is a highly heterogeneous condition comprising neuropathic, nociceptive and inflammatory components, and patient responses to currently available drugs vary greatly. A very promising approach to target various forms of pain is through antagonism of key players in neuro- inflammation. Specifically, the chemokine receptor system, a complex network of over 20 different receptors and over 80 ligands, is integral to neuroinflammatory processes and the pharmaceutical industry had been very active in developing compounds targeting individual receptors in the network. However, the biological complexity, ligand promiscuity, and receptor redundancy of the chemokine receptor system has precluded successful clinical development of the compounds and many pharma have exited the pain therapeutic area. A major limitation of successful targeting of this network is sufficient understanding of the molecular and cellular dynamics of the chemokine network, and how specific receptors vary in chronic pain conditions. In this study, we aim to determine the genetic expression of a chemokine receptor utilizing human clinical samples collected in a clinical trial evaluating a receptor antagonist. Further, we will utilize this understanding in conjunction with patient efficacy data from the clinical trials to continue the development of our lead compound, a drug that showed a statistically significant clinical signal in pain. Results from this study will enable patient stratification and effective clinical trial design by including patients with the appropriate genetic and phenotypic background and thus significantly increase the likelihood achieving primary endpoints of pain reduction in the clinic.