CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis

CMA：减轻关节炎疼痛的软骨修复策略 (CaRe AP)：基于新型细胞的疗法，可提高骨关节炎临床前模型的功能结果并减轻疼痛

• 批准号: 10292959
• 负责人: HICHAM M DRISSI
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292959
• 关键词: Activities of Daily Living; Address; Adipose tissue; Adolescent; Adult; Affect; Afferent Neurons; Animal Model; Animals; Arthralgia; Arthritis; Autologous; BMP2 gene; Biological; Bone Marrow; Caring; Cartilage; Cell Therapy; Cells; Chondrocytes; Chronic; Clinical Trials; Cumulative Trauma Disorders; Data; Defect; Degenerative polyarthritis; Development; Disease; Evaluation; Exercise; Fibrocartilages; Gait; Goals; Gunshot wound; Histologic; Human; Hyaline Cartilage; In Vitro; Individual; Inflammation; Inflammatory; Infrastructure; Injury; Joints; Knee; Label; Laboratories; Lead; Left; Link; Mechanics; Mesenchymal Stem Cells; Modality; Modeling; Movement; Muscle Weakness; Natural Immunity; Natural regeneration; Nerve Endings; Neurologic; Nociception; Operative Surgical Procedures; Pain; Pain Measurement; Pain management; Particulate; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Physical Exercise; Physical Rehabilitation; Physical therapy; Physiology; Pluripotent Stem Cells; Pre-Clinical Model; Rattus; Regenerative capacity; Regimen; Rehabilitation therapy; Reporting; Research; Research Personnel; Running; Sequential Treatment; Social Impacts; Somatic Cell; Source; Spinal Ganglia; Standardization; Structure; Swelling; Synovitis; Testing; Therapeutic; Tissue Engineering; Treatment outcome; Vertebral column; Veterans; War; Weight-Bearing state; adult stem cell; allodynia; arthritic pain; articular cartilage; base; cartilage degradation; cartilage regeneration; cartilage repair; central pain; chronic pain; common treatment; comparative efficacy; density; experimental study; functional outcomes; immunoregulation; implantation; improved; improved functioning; in vivo; induced pluripotent stem cell; inhibitor; innovation; joint function; joint injury; loss of function; military service; molecular imaging; muscle strength; novel; osteoarthritis pain; pain inhibition; pain outcome; pain reduction; pain relief; patient population; peptidomimetics; preservation; prevent; programs; reconstruction; repair strategy; repaired; response; restoration; service member; small molecule; socioeconomics; standard of care; stem cell therapy; stem cells; subchondral bone; tissue regeneration; tissue repair; treatment response

Overall Research Strategy: The overall goal of the CaRa-AP Collaborative Program is to develop a treatment for post-traumatic osteoarthritis (PTOA) that will relieve pain and improve function. We hypothesize that PTOA is caused by maladaptive repair responses including activation of the pro-inflammatory pathways of innate immunity that in turn result in pain, loss of function and structural decline. This Program addresses the hypothesis through two highly-integrated aims: (1) innovative intra-articular treatments using small molecules, biologic inhibitors and immunomodulatory cells to reduce pain and inflammation in the joint and (2) tissue engineering using stem cell-based therapies for reconstruction of the damaged joint infrastructure. The investigators collaborating in this program will coordinate testing of therapies in four animal models that mimic different mechanisms of injury that initiate PTOA in patients. The experiments will take into consideration relevant factors affecting joint physiology and treatment response. The effects of different therapeutic modalities will be evaluated using group-standardized measurements of pain, function, inflammation and structure, so that results can be compared across laboratories and the most promising therapeutic strategies prioritized for clinical trials. We provide compelling evidence that sequential treatment of mesenchymal progenitors with BMP2 and non- canonical Wnt5a, cultured in high density pellets, yield articular-like cells in vitro. These effects are reproduced when small molecules Kartogenin (KGN), a chondrogenic small molecule targeting Runx1, and Foxy5, a Wnt5a mimetic peptide, are sequentially used. Moreover, implantation of pellets, treated with BMP2 followed by Wnt5a, into a rat chondral defect regenerate articular-like cartilage. Our preliminary data also demonstrate an influence of physical exercise on cartilage preservation and joint function in a rat model of PTOA. Thus, we ask whether the source of stem cells can differentially promote hyaline cartilage regeneration and if physical rehabilitation can improve pellet integration and treatment outcome. Specifically, we aim to compare the efficacy of somatic cells (human articular chondrocytes and bone marrow derived mesenchymal stem cells) to that of patient- specific, and readily available, pluripotent stem cells. We hypothesize that cell plasticity will determine the potential of adult versus pluripotent stem cells to treat cartilage degeneration, and that successful restoration of cartilage integrity via cellular and physical therapy will lead to enhanced functional outcomes and reduced nociception in vivo. We will first establish the capacity of iPSC-derived MSCs to that of adipose-derived and human articular cartilage MSCs with and without sequential treatment with KGN and Foxy5 to regenerate articular cartilage following implantation of control or treated high-density pellets into a rat chondral defect model of PTOA. Histological evaluations, matrix synthesis, mechanical testing and molecular imaging analyses will be performed (Aim 1). We will then assess the effect of cellular and physical treatment of animals on long-term functional, nociceptive, and centralized pain outcomes. We will evaluate functional outcomes in control and experimental rats that receive either iPSC-derived MSCs or the most effective adult stem cell source identified in Aim 1. Specifically, gait, voluntary running, muscle strength, mechanical testing, and allodynia analyses will also be performed. We will also assess the neurological changes that often lead to chronic joint pain (Aim 2).

总体研究策略：CaRa-AP 合作项目的总体目标是开发一种治疗方法 用于治疗创伤后骨关节炎 (PTOA)，可缓解疼痛并改善功能。我们假设 PTOA 是由适应不良修复反应引起的，包括先天促炎症途径的激活 免疫力进而导致疼痛、功能丧失和结构衰退。该程序解决了假设 通过两个高度整合的目标：（1）使用小分子、生物制剂的创新关节内治疗 抑制剂和免疫调节细胞，以减轻关节疼痛和炎症；(2) 组织工程 使用干细胞疗法重建受损的关节基础设施。调查人员 该项目中的合作将协调在四种模拟不同动物模型的疗法测试 引发患者 PTOA 的损伤机制。实验将考虑相关因素 影响关节生理和治疗反应。将评估不同治疗方式的效果 使用疼痛、功能、炎症和结构的团体标准化测量，以便结果可以 比较各个实验室和优先用于临床试验的最有前途的治疗策略。 我们提供了令人信服的证据，证明用 BMP2 和非-间充质祖细胞序贯治疗 典型的 Wnt5a 在高密度颗粒中培养，可在体外产生关节样细胞。再现这些效果 小分子 Kartogenin (KGN)（一种靶向 Runx1 的软骨形成小分子）和 Foxy5（一种 Wnt5a） 依次使用模拟肽。此外，植入用 BMP2、随后用 Wnt5a 处理的颗粒， 使大鼠软骨缺损再生出关节样软骨。我们的初步数据也表明了影响 体育锻炼对 PTOA 大鼠模型软骨保存和关节功能的影响。因此，我们问是否 干细胞的来源可以差异性地促进透明软骨再生以及身体康复 可以改善颗粒整合和治疗效果。具体来说，我们的目的是比较体细胞的功效 细胞（人关节软骨细胞和骨髓来源的间充质干细胞）与患者的细胞 特定且容易获得的多能干细胞。我们假设细胞可塑性将决定 成人干细胞与多能干细胞治疗软骨退化的潜力，并且成功 通过细胞和物理疗法恢复软骨完整性将导致功能增强 结果并减少体内伤害感受。 我们将首先确定 iPSC 来源的 MSC 与脂肪来源和人类关节细胞的能力 使用和不使用 KGN 和 Foxy5 序贯治疗的软骨 MSC 再生关节软骨 将对照或处理过的高密度颗粒植入 PTOA 大鼠软骨缺损模型后。 将进行组织学评估、基质合成、机械测试和分子成像分析 （目标 1）。然后我们将评估动物的细胞和物理治疗对长期的影响 功能性、伤害性和集中性疼痛结果。我们将评估控制和功能结果 实验大鼠接受 iPSC 衍生的 MSC 或已确定的最有效的成体干细胞来源 目标 1。具体来说，步态、自愿跑步、肌肉力量、机械测试和异常性疼痛分析将 也可进行。我们还将评估经常导致慢性关节疼痛的神经系统变化（目标 2）。