Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of Chronic Pancreatitis and Its Associated Pain

间充质干细胞治疗慢性胰腺炎及其相关疼痛的安全性和有效性

• 批准号: 10721284
• 负责人: Hongjun Wang
• 金额: $ 32.76万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10721284
• 关键词: Abdominal Pain; Accreditation; Acinar Cell; Acute Pain; Adverse event; Aftercare; Allogenic; Animal Model; Animals; Anti-Inflammatory Agents; Anxiety; Apoptotic; Autoimmune Diseases; Biochemical Pathway; Bone Marrow; Cell Death; Cell Therapy; Cell physiology; Cessation of life; Choristoma; Chronic; Clinical Trials; Clinical Trials Data Monitoring Committees; Cyclic GMP; Data; Diabetic Neuropathies; Disease; Disease Marker; Disease remission; Double-Blind Method; Fibrosis; Functional disorder; Goals; Harvest; Human; Hypersensitivity; Immunophenotyping; Inflammation; Inflammatory; Informed Consent; Infusion procedures; Injections; Injury; Institutional Review Boards; Interdisciplinary Study; Intervention; Intestines; Knee Osteoarthritis; Manuals; Measures; Mental Depression; Mesenchymal Stem Cells; Mitotic; Morphology; Multiple Trauma; Mus; Narcotics; Neurologic; Neuropathy; Opiate Addiction; Opioid; Overdose; Oxidative Stress; Pain; Pancreas; Pathway interactions; Patient Outcomes Assessments; Patients; Peripheral Blood Mononuclear Cell; Persons; Phase; Prefrontal Cortex; Preparation; Protocols documentation; Quality of life; Risk; Rodent Model; Safety; Serum; Spinal Cord; Statistical Data Interpretation; Symptoms; Syndrome; Testing; Therapeutic; Tissues; Visceral; addiction; adult stem cell; animal data; cell bank; cell motility; cell preparation; cell type; central sensitization; chronic pain; chronic pancreatitis; critical limb Ischemia; cytokine; experience; immunoregulation; improved; improved outcome; insight; mesenchymal stromal cell; metabolomics; monocyte; mouse model; novel; novel strategies; operation; pain reduction; pain relief; pharmacologic; protective effect; randomized placebo-controlled clinical trial; response biomarker; safety testing; single-cell RNA sequencing; treatment strategy

Abstract: Chronic pancreatitis (CP) is a debilitating disease characterized by irreversible morphological changes (fibrosis) and persistent inflammation in the pancreas. Abdominal pain is one of the predominant symptoms and presents in up to 90% of CP patients and is associated with the heavy use of opioids. Chronic pain can cause opioid dependence, anxiety, depression and reduced quality of life. Although opioids are effective for acute pain, they are not effective as a long-term treatment strategy. There is a critical need for more effective, safer, and non- addictive therapeutic options for people who suffer from chronic pain associated with CP or other diseases. The use of mesenchymal stromal cells (MSCs) in treating pain represents a promising novel intervention as increasing evidence demonstrates that MSC therapy can effectively target several injury pathways in a variety of fibroinflammatory diseases while reducing pain, something that most pharmacological interventions cannot accomplish. MSCs exert protective effects through the release of pro-mitotic, antiapoptotic, anti-inflammatory, and immunomodulatory soluble factors, to mitigate metabolomic and oxidative stress imbalance. Data from animal models and clinical trials support the outstanding and durable effects of MSC infusion in the suppression of chronic inflammation and neurological pain associated with various diseases. Our own animal study demonstrated that MSC infusion significantly reduces pain and improves fibrosis and pancreatic volume in mouse models of CP. However, whether the infusion of MSCs can be used as a novel approach to relieving chronic pain and improve pancreatic function in CP patients has not been tested and will be the focus of this study. Based on compelling data, our hypothesis is that treatment with MSCs reduces chronic pain and improves pancreatic fibrosis and function by their ability to target multiple injury pathways. The objective of this study is two folds: (i) prepare for the clinical trial (UG3 phase, year 1), and determine the safety and efficacy of MSC therapy in patients with painful CP (UH3 phase, year 2-5). Another critical part of the clinical trial phase will be to define the mechanisms by which MSCs relieve multiple injuries in the pancreas by measuring changes of peripheral blood mononuclear cells (PBMCs), especially monocyte subsets and serum proinflammatory cytokine profiles of treated patients, with the goal of identifying biochemical pathways and serum biomarkers of response to MSC therapy. This study may help develop novel non-addictive cellular therapy for chronic pancreatitis and pain.

抽象的： 慢性胰腺炎（CP）是一种使人衰弱的疾病，其特征是不可逆的形态变化（纤维化） 和胰腺持续的炎症。腹痛是主要的症状，并出现 在多达90％的CP患者中，与大量使用阿片类药物有关。慢性疼痛会导致阿片类药物 依赖，焦虑，抑郁和生活质量降低。尽管阿片类药物对急性疼痛有效，但 作为长期治疗策略无效。迫切需要更有效，更安全和非 - 与CP或其他疾病有关的慢性疼痛患者的上瘾治疗选择。 间充质基质细胞（MSC）在治疗疼痛中的使用表示有希望的新干预措施 越来越多的证据表明，MSC治疗可以有效地针对多种伤害途径 减轻疼痛的肌炎性疾病，大多数药理学干预措施不能 完成。 MSC通过释放促有丝分裂，抗凋亡，抗炎，发挥保护作用 和免疫调节可溶性因子，以减轻代谢组和氧化应激失衡。来自 动物模型和临床试验支持MSC输注在抑制中的出色和持久作用 与各种疾病相关的慢性炎症和神经系统疼痛。我们自己的动物研究 证明MSC输注可显着减轻疼痛并改善纤维化和胰腺体积 CP的鼠标模型。但是，输注MSC是否可以用作缓解的新方法 尚未测试CP患者的慢性疼痛和改善胰腺功能 学习。 基于引人注目的数据，我们的假设是MSC的治疗可减轻慢性疼痛并改善 胰腺纤维化和靶向多个损伤途径的能力。这项研究的目的是 两折：（i）准备临床试验（UG3阶段，第1年），并确定MSC的安全性和功效 CP疼痛患者的治疗（UH3期，2 - 5年）。临床试验阶段的另一个关键部分是 定义MSC通过测量变化的变化来缓解胰腺多重伤害的机制 外周血单核细胞（PBMC），尤其是单核细胞集和血清促炎细胞因子 治疗患者的特征，目的是鉴定生化途径和血清生物标志物 进行MSC治疗。这项研究可能有助于开发新的非添加性细胞疗法，用于慢性胰腺炎和 疼痛。