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

人体临床试验生物样本中疼痛性糖尿病神经病变的趋化因子受体分析

• 批准号: 10326651
• 负责人: Thomas P Richardson
• 金额: $ 70.01万
• 依托单位: PLUMERIA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326651
• 关键词: Affect; Alternative Splicing; Amino Acid Sequence; Applications Grants; Area; Attenuated; Biological; Biological Assay; C-terminal; Clinic; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Complex; Data; Development; Diabetes Mellitus; Diabetic Neuralgia; Diagnostic Reagent Kits; Drug Antagonism; Drug Industry; Genetic; Healthcare; Heart Diseases; Human; Individual; Inflammation; Inflammatory; Investigational Drugs; Investments; Journals; Knock-out; Laboratories; Lead; Ligands; Malignant Neoplasms; Measures; Medical; Messenger RNA; Methods; Molecular; Neuropathy; Nociception; Outcome; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phase II Clinical Trials; Phenotype; Physicians; Play; Population Heterogeneity; Process; Product Labeling; Protein Isoforms; Publishing; Quality of life; Receptor Gene; Role; Sampling; Serum; Signal Transduction; Small Business Innovation Research Grant; Source; System; Therapeutic; Transgenic Mice; Treatment outcome; Work; base; chemokine; chemokine receptor; chronic pain; chronic painful condition; clinical development; clinical diagnostics; companion diagnostics; diabetic patient; drug development; economic cost; follow-up; genetic profiling; in-vitro diagnostics; inclusion criteria; mRNA Precursor; material transfer agreement; monocyte chemoattractant protein 1 receptor; neuroinflammation; pain patient; pain reduction; pain relief; painful neuropathy; patient population; patient response; patient stratification; phase 1 study; phase 2 study; phase II trial; population based; primary endpoint; programs; receptor; receptor expression; research clinical testing; responders and non-responders; response; secondary endpoint; success; therapeutic target; tool

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.

项目摘要/摘要 慢性疼痛是主要的医疗负担，每年的经济成本高达6350亿美元，甚至更多 根据约翰·霍普金斯大学发表在《疼痛杂志》上的一项研究，癌症、糖尿病和心脏病比癌症、糖尿病和心脏病更重要。 疼痛是一种高度异质性的疾病，由神经性、伤害性和炎症性成分组成， 而且患者对目前可用的药物的反应差异很大。 一种非常有希望的针对各种形式的疼痛的方法是通过对抗神经中的关键角色- 发炎。具体地说，趋化因子受体系统，一个由20多个不同受体和 超过80个配体，是神经炎性过程中不可或缺的一部分，制药行业一直非常活跃 在开发针对网络中单个受体的化合物方面。然而，生物的复杂性， 趋化因子受体系统的配体错乱和受体冗余阻碍了临床的成功 化合物和许多药物的开发已经离开了疼痛治疗领域。 成功靶向这个网络的一个主要限制是对分子和 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如何变化。在这 在这项研究中，我们的目标是利用人类临床样本来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，我们将利用这一理解在 结合临床试验中的患者疗效数据，继续开发我们的先导化合物， 一种对疼痛有统计意义的临床信号的药物。这项研究的结果将使患者 通过纳入具有适当基因和表型的患者进行分层和有效的临床试验设计 背景，并因此显著增加实现减少疼痛的主要终点的可能性 诊所。