A first in class, mechanism-guided, cell-based therapy for complex regional pain syndrome

针对复杂区域疼痛综合征的一流、机制引导、基于细胞的疗法

• 批准号: 10572041
• 负责人: JIANGUO CHENG
• 金额: $ 203.31万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572041
• 关键词: Address; Adipose tissue; Adult; American; Analgesics; Animal Model; Animals; Apoptotic; Autoimmune Process; Autoimmunity; Biological; Biological Markers; Bone Marrow; Cell Therapy; Cells; Clinic; Clinical; Clinical Treatment; Clinical Trials; Clinical Trials Data Monitoring Committees; Clinical Trials Design; Clinical trial protocol document; Cognitive; Complex Regional Pain Syndromes; Consultations; Cyclic GMP; Data; Data Analyses; Development; Disease; Dose; Experimental Designs; Future; Growth Factor; Homing; Human; Immunoglobulin G; Institutional Review Boards; Intervention; Investigation; Investigational Drugs; Investigational New Drug Application; Measures; Medicine; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metabolic; Mitochondria; Modeling; Musculoskeletal; Neuroimmune; New Drug Approvals; Operative Surgical Procedures; Opioid; Outcomes Research; Pain; Pain management; Paracrine Communication; Pathogenesis; Pathology; Patients; Phase; Play; Positioning Attribute; Preclinical Testing; Process; Property; Publishing; Quality Control; Rattus; Refractory; Research; Role; Safety; Signal Transduction; Somatotropin; Source; Symptoms; Technology; Testing; Tissues; Translating; Treatment Efficacy; Treatment Protocols; Umbilical cord structure; United States National Institutes of Health; base; behavioral pharmacology; bench to bedside; bench-to-bedside translation; burden of illness; chronic constriction injury; chronic pain; chronic pain management; chronic painful condition; clinical practice; cost; cost effective treatment; disability; effective therapy; efficacious treatment; exosome; human stem cells; human subject; immunoregulation; improved functioning; in vitro Assay; innovation; microvesicles; mouse model; multidisciplinary; novel; novel therapeutics; optimal treatments; pain reduction; painful neuropathy; preclinical study; preclinical trial; predict clinical outcome; prototype; sciatic nerve injury; stem cell biology; stem cell therapy; study population; symptomatic improvement; trafficking; treatment optimization; treatment strategy

Chronic pain afflicts more than 50 million American adults and costs our nation an estimated $560 to $635 billion annually. Complex regional pain syndrome (CRPS) represents one of the most disabling and difficult-to- treat chronic pain conditions in clinical practice. Management of CRPS is one of the greatest challenges in the field of pain management. Novel and more efficacious treatment strategies are urgently needed to relieve the burden of pain, suffering, and disability caused by CRPS. To address this unmet need, we propose to develop a first-in-class, mechanism-guided, and cell-based treatment for CRPS using human mesenchymal stem cells (hMSCs). Based upon strong biological rationale and ample supporting data, we hypothesize that hMSC transplantation significantly improves the symptoms and distinctly modifies the disease processes of CRPS through neuroimmune-modulatory and analgesic effects of MSCs. In this bench-to-bedside translational investigation, we aim to generate clinical-grade hMSCs derived from the bone marrow, adipose, and umbilical cord tissues, to optimize hMSC treatment protocols in terms of source and dose of hMSCs, and to gain Investigational New Drug (IND) approval for clinical trials. We further aim to conduct a pilot clinical trial to determine the safety and efficacy of hMSC therapy in reducing pain and improving function in patients with CRPS. As an architype of neuropathic pain (NP) and a prototype of a new type of autoimmunity, CRPS is an ideal disease to study for innovative strategies to treat NP. The use of hMSCs represents a golden opportunity to treat CRPS and to advance this technology to human patients, which is strongly supported by our published and preliminary data. This project is innovative because the use of MSCs to treat CRPS has never been studied. We propose novel experimental designs to optimize the source and dose of MSC therapy through synergistic preclinical and clinical trials to determine the scientific rationale for future MSC treatment clinical trial protocols. The proposed pilot clinical trial represents the first-in-class and mechanism-guided human trial of a novel MSC treatment not only for CRPS, but also for other NP conditions. We will use the novel and sensitive in vitro assays we have developed to assess the neuroimmune modulatory properties of hMSCs, to serve as a measure of quality control, and to predict clinical outcomes of hMSC therapy. Our interdisciplinary team with complementary expertise in stem cell biology, pain management, pre-clinical testing, and outcomes research, is uniquely positioned to successfully implement this project. Successful completion of the project will deliver a safe, efficacious, non-addictive, and cost-effective treatment for patients with refractory CRPS. By addressing the unmet needs of CRPS patients through bench-to-bedside translation, this novel therapy promises to be a game- changer that would fundamentally shift the paradigm in the management of CRPS. In addition, the study will generate treatment protocols that can conceivably be utilized to treat patients with a wide range of other refractory NP conditions.

慢性疼痛困扰着5000多万美国成年人，每年给我们国家造成的损失估计为5600亿至6350亿美元。复杂性局部疼痛综合征（CRPS）是临床实践中最难治疗的慢性疼痛疾病之一。CRPS的管理是疼痛管理领域的最大挑战之一。迫切需要新的和更有效的治疗策略来减轻CRPS引起的疼痛、痛苦和残疾的负担。为了解决这一未满足的需求，我们建议使用人间充质干细胞（hMSCs）开发一种一流的、机制指导的、基于细胞的CRPS治疗方法。基于强有力的生物学原理和充足的支持数据，我们假设hMSC移植显著改善了CRPS的症状，并通过MSC的神经免疫调节和镇痛作用明显改变了CRPS的疾病过程。在这项从实验室到床边的转化研究中，我们的目标是从骨髓、脂肪和脐带组织中产生临床级的hMSC，以优化hMSC的来源和剂量方面的hMSC治疗方案，并获得临床试验的研究性新药（IND）批准。我们进一步的目标是进行一项试点临床试验，以确定hMSC治疗在减轻CRPS患者疼痛和改善功能方面的安全性和有效性。CRPS作为神经病理性疼痛的一种原型和一种新型自身免疫性疾病的原型，是研究神经病理性疼痛治疗策略的理想疾病。hMSCs的使用代表了治疗CRPS并将该技术推向人类患者的黄金机会，这得到了我们已发表和初步数据的有力支持。这个项目是创新的，因为使用MSC治疗CRPS从未被研究过。我们提出了新的实验设计，通过协同临床前和临床试验优化MSC治疗的来源和剂量，以确定未来MSC治疗临床试验方案的科学依据。拟议中的试点临床试验代表了一类新型MSC治疗的首次机制指导的人体试验，不仅用于CRPS，还用于其他NP条件。我们将使用我们已经开发的新型和敏感的体外试验来评估hMSC的神经免疫调节特性，作为质量控制的措施，并预测hMSC治疗的临床结果。我们的跨学科团队在干细胞生物学，疼痛管理，临床前测试和结果研究方面具有互补的专业知识，能够成功实施该项目。该项目的成功完成将为难治性CRPS患者提供安全，有效，非成瘾和具有成本效益的治疗。通过通过从实验室到床边的转化来解决CRPS患者未满足的需求，这种新型疗法有望成为一种改变游戏规则的方法，从根本上改变CRPS管理的模式。此外，该研究将产生治疗方案，可以想象用于治疗患有广泛的其他难治性NP疾病的患者。