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