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

慢性疼痛折磨着5000多万美国成年人，每年给我们国家造成的损失估计在5600亿到6350亿美元之间。复杂区域疼痛综合征（CRPS）是临床实践中最致残和最难治疗的慢性疼痛症状之一。CRPS的管理是疼痛管理领域最大的挑战之一。迫切需要新的和更有效的治疗策略来减轻由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，我们建议利用人间充质干细胞（hMSCs）开发一种一流的、机制引导的、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移植通过MSCs的神经免疫调节和镇痛作用显著改善CRPS的症状并明显改变疾病过程。在这项从实验室到临床的转化研究中，我们的目标是从骨髓、脂肪和脐带组织中产生临床级hMSCs，在hMSCs的来源和剂量方面优化hMSC治疗方案，并获得临床试验新药（IND）批准。我们进一步的目标是开展一项试点临床试验，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是神经性疼痛（NP）的一种基础类型，是一种新型自身免疫的原型，是研究神经性疼痛创新治疗策略的理想疾病。使用hMSCs是治疗CRPS的黄金机会，并将这项技术推广到人类患者，这得到了我们已发表和初步数据的大力支持。该项目具有创新性，因为使用间充质干细胞治疗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来优化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。拟议的试点临床试验代表了一种新型MSC治疗的一流和机制指导的人体试验，不仅适用于CRPS，也适用于其他NP疾病。我们将使用我们开发的新颖灵敏的体外检测来评估骨髓间充质干细胞的神经免疫调节特性，作为质量控制的衡量标准，并预测骨髓间充质干细胞治疗的临床结果。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，具有成功实施该项目的独特优势。该项目的成功完成将为难治性CRPS患者提供一种安全、有效、无成瘾性和具有成本效益的治疗方法。通过从临床到临床的转化，解决了CRPS患者未满足的需求，这种新疗法有望成为一种游戏规则改变者，从根本上改变CRPS管理模式。此外，该研究将产生治疗方案，可用于治疗范围广泛的其他难治性NP疾病患者。

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.