Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells

中和退化的椎间盘微环境以增强治疗干细胞的功效

• 批准号: 10337343
• 负责人: Neil Malhotra
• 金额: $ 54.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337343
• 关键词: Address; Adopted; Animal Model; Anti-Inflammatory Agents; Biological Assay; Biological Response Modifier Therapy; Biomechanics; Buffers; Cell physiology; Cells; Characteristics; Chondroitin ABC Lyase; Clinical; Clinical Trials; Coupled; Dose; Drug Delivery Systems; Failure; Functional Regeneration; Glucose; Goals; Goat; Human; Human Characteristics; In Situ; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injections; Intervertebral disc structure; Longitudinal Studies; Low Back Pain; Measures; Mechanics; Mediating; Mesenchymal Stem Cells; Methods; Microcapsules drug delivery system; Modeling; Nutrient; Oxygen; Pain Measurement; Performance; Pharmaceutical Preparations; Phenotype; Physiologic Monitoring; Physiological; Positioning Attribute; Safety; Series; Severities; Structure; Symptoms; System; Therapeutic; Therapeutic Intervention; Time; Tissues; Treatment Efficacy; United States; base; clinical application; clinically relevant; cost; cytokine; design; disability; disc regeneration; implantation; improved; in vivo; intervertebral disk degeneration; novel; novel therapeutics; nucleus pulposus; nutrition; pain patient; pain symptom; pre-clinical; preclinical efficacy; quantitative imaging; regeneration potential; restoration; socioeconomics; stem cell survival; stem cell therapy; stem cells; symptom management; tool

Abstract Low back pain is the leading cause of disability in the United States, with an estimated socioeconomic cost exceeding $100 billion each year. Intervertebral disc degeneration, a cascade of cellular, compositional, structural and compositional changes, is strongly implicated as a cause of low back pain. Current clinical approaches for treating low back pain associated with disc degeneration have limited long term efficacy as they seek only to manage symptoms without restoring native disc structure and mechanical function. There is an overwhelming clinical need for new treatment options, which target not only the symptoms of low back pain, but also the underlying causes. Mesenchymal stem cells (MSCs) are an attractive option for cell- based disc regeneration due to their safety, ease of isolation and ability to adopt phenotypes similar to those of disc nucleus pulposus cells. A major challenge to successful MSC-based disc regeneration, however, is the local cellular microenvironment, which presents conditions of limited nutrition, low oxygen, low pH, and persistent inflammation that predispose therapeutic interventions to failure. The objective of this proposal is to develop a novel biological therapy that maximizes the survival and anabolic potential of therapeutic stem cells by simultaneously neutralizing the degenerate disc microenvironment via the sustained delivery of nutrients, anti-inflammatory drugs and buffering agents. To accomplish this goal, we will leverage our newly established goat model of disc degeneration that mimics clinically relevant structural, composition and biomechanical characteristics, including tissue-level inflammation, and novel drug delivery methods to enable controlled and sustained release of biofactors that neutralize the degenerative microenvironment. In Aim 1 we will leverage our goat model define the in vivo cellular microenvironment of the disc as a function of degeneration severity, using cutting edge in situ physiological monitoring and ex vivo biomolecular assays. In Aim 2 we will optimize our novel microcapsule drug delivery system to neutralize the degenerate disc microenvironment through sustained delivery of glucose, anti- inflammatory drugs and buffering agents. In Aim 3 we will carry out short and long term in vivo studies to establish therapeutic efficacy in our goat model, including clinically-relevant pain assessments. At the conclusion of these studies we will have developed a rapidly translatable therapy that maximizes the regenerative potential of MSCs in the disc microenvironment, and established long term preclinical efficacy, thus placing us in a strong position to move towards human clinical trials.

抽象的 腰痛是美国残疾的主要原因，估计会造成社会经济损失 每年超过1000亿美元。椎间盘退变是一系列细胞、成分、 结构和成分的变化，与腰痛的原因密切相关。目前临床 治疗与椎间盘退变相关的腰痛的方法的长期疗效有限，因为 他们只寻求控制症状，而不恢复天然椎间盘结构和机械功能。有 临床迫切需要新的治疗方案，这些方案不仅针对低血压症状 腰痛，也是根本原因。间充质干细胞 (MSC) 是细胞治疗的一个有吸引力的选择 基于椎间盘再生的安全性、易于分离以及采用与椎间盘再生相似的表型的能力 椎间盘髓核细胞。然而，基于 MSC 的椎间盘再生成功的一个主要挑战是 局部细胞微环境，呈现营养有限、低氧、低pH值和 持续的炎症使治疗干预容易失败。该提案的目标是 开发一种新型生物疗法，最大限度地提高治疗药物的存活率和合成代谢潜力 干细胞通过持续的作用同时中和退化的椎间盘微环境 输送营养物质、抗炎药物和缓冲剂。为了实现这一目标，我们将 利用我们新建立的模拟临床相关的椎间盘退变山羊模型 结构、成分和生物力学特征，包括组织水平炎症，以及 新颖的药物输送方法，能够控制和持续释放中和的生物因子 退化的微环境。在目标 1 中，我们将利用我们的山羊模型定义体内细胞 使用前沿的原位生理学技术，将椎间盘的微环境作为退变严重程度的函数 监测和离体生物分子测定。在目标 2 中，我们将优化我们的新型微胶囊药物输送 系统通过持续输送葡萄糖来中和退化的椎间盘微环境，抗 消炎药和缓冲剂。在目标 3 中，我们将进行短期和长期体内研究 在我们的山羊模型中建立治疗效果，包括临床相关的疼痛评估。在 根据这些研究的结论，我们将开发出一种可快速转化的疗法，最大限度地提高治疗效果。 间充质干细胞在椎间盘微环境中的再生潜力，并建立了长期临床前研究 功效，从而使我们在人体临床试验方面处于有利地位。