The Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis

使用Senolytic和抗纤维化药物提高骨髓干细胞对骨关节炎的有益作用

• 批准号: 10416892
• 负责人: Johnny Huard
• 金额: $ 15.65万
• 依托单位: STEADMAN PHILIPPON RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416892
• 关键词: Adipose tissue; Adult; Aftercare; Age; Allografting; Apoptosis; Apoptotic; Aspirate substance; Autologous; Biological Markers; Biological Response Modifier Therapy; Blood; Bone Marrow; Bone Marrow Stem Cell; Cartilage; Cartilage Diseases; Cell Aging; Cell Death; Cells; Chondrocytes; Clinic; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Degenerative polyarthritis; Development; Disease; Double-Blind Method; Drug usage; FDA approved; Fibrocartilages; Fibrosis; Goals; Grant; Harvest; Homeostasis; Hyaline Cartilage; Image; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Injury; Intervention; Investigation; Joints; Kinetics; Knee Osteoarthritis; Knee joint; Laboratories; Losartan; Magnetic Resonance Imaging; Metabolic; Morphology; Motion; Mus; Natural regeneration; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Patient Outcomes Assessments; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Phase I/II Trial; Phenotype; Pre-Clinical Model; Progressive Disease; Randomized; Randomized Clinical Trials; Regimen; Replacement Arthroplasty; Research Institute; Research Personnel; Resistance; Safety; Signal Transduction; Skeletal Muscle; Structure; Synovial Fluid; Technology; Time; Tissues; Transforming Growth Factor alpha; Transforming Growth Factors; Transplantation; Treatment Efficacy; Treatment outcome; Work; adult stem cell; adult stem cell transplantation; arm; arthropathies; articular cartilage; base; cartilage degradation; cartilage repair; cell type; chemokine; clinical efficacy; clinically translatable; cytokine; design; dietary supplements; fisetin; implantation; improved; improved outcome; inhibitor/antagonist; joint destruction; kinematics; loss of function; minimally invasive; novel strategies; osteochondral tissue; pain outcome; patient population; pre-clinical; prevent; regeneration potential; repaired; senescence; stem cell function; stem cell therapy; stem cells; symptom treatment

Abstract: Osteoarthritis (OA) is a progressive joint disease leading to cartilage damage, pain and loss of function. While many stem cell therapies for OA are under investigation, none are currently FDA-approved for modifying the course of the disease. Of the many adult stem cell types potentially applicable to OA, bone marrow stem cells (BMSCs) from bone marrow aspirate concentrate (BMC) are the most clinically translatable (and are already in clinical use) since they can be harvested using minimally invasive technology and do not require in vitro expansion. There is, however, significant potential for improving efficacy of BMSC treatment for OA. The number of senescent cells in BMC increases with age and OA, and these cells release pro-inflammatory cytokines/chemokines, proteases, and other senescence-associated secretory phenotypes (SASP) that can impair stem cell function and likely contribute to OA development/progression. Dr. Kirkland’s laboratory (co- investigator) has identified compounds that specifically kill senescent cells, abrogating systemic SASP factors. We have shown that these senolytic agents can delay OA in a preclinical model. We have also shown that blocking fibrosis with Losartan (a TGF-β1blocker) can improve cartilage repair by promoting regeneration of hyaline cartilage while reducing the amount of fibrocartilage. Thus, we hypothesize that administration of senolytic and/or anti-fibrotic agents will enhance the beneficial effect of BMSCs for treating OA. We propose to perform, a randomized clinical trial at The Steadman Clinic (TSC) and Steadman Philippon Research Institute (SPRI). This phase I/II trial will evaluate the safety and efficacy of Fisetin (a senolytic dietary supplement) and Losartan (an anti-fibrotic drug), used either individually or in combination, for improving the clinical efficacy of BMSCs in the treatment of knee osteoarthritis. The senolytic (Fisetin 1000mg/day, previously FDA IND approved) regimen will be cycles of 2 days on/28 days off, administered before and 3 months after BMSC treatment. The anti-fibrotic (Losartan, 25mg/day, previously IND-exempted) will be administered for 30 days starting immediately after BMSC treatment. OA knee joints will undergo MRI at baseline and 18 months post- treatment to assess changes in cartilage morphology and structure over time. Patient-reported outcomes for pain and function will be collected at baseline and 3, 6, 12 & 18 months. Joint and cartilage function will be assessed using video-motion analysis at baseline and 18 months. OA biomarkers related to cartilage degeneration, inflammation and pain will be assessed at baseline and 18 months. Blood and synovial fluid will be evaluated at baseline, 4 days and 18 months after treatment to assess changes in cellular senescence and OA biomarkers. This trial will build upon a currently active clinical trial on orthobiologics for OA treatment at SPRI (utilizing the same patient population and outcomes assessments), demonstrating the ability of our teams to perform the proposed study and also leveraging the combined trials to effectively provide a 6-arm, comprehensive assessment of biological therapies for improving treatment of OA.

摘要：骨关节炎（OA）是一种进行性关节疾病，导致软骨损害，疼痛和丧失 功能。虽然许多OA的干细胞疗法正在研究中，但目前没有FDA批准 修改疾病的病程。在许多可能适用于OA的成年干细胞类型中，骨髓 来自骨髓抽吸物浓缩液（BMC）的干细胞（BMSC）是临床上最可转换的（并且是 已经在临床上使用），因为可以使用微创技术收集它们，并且不需要 体外扩张。但是，提高OA的BMSC处理效率有很大的潜力。 BMC中的感觉细胞的数量随着年龄和OA而增加，这些细胞释放了促炎 细胞因子/趋化因子，蛋白酶和其他相关的秘书表型（SASP）可以 损害干细胞功能，可能有助于OA的发展/进展。柯克兰博士的实验室（共同 研究者）已经确定了专门杀死感觉细胞的化合物，从而消除了全身性SASP因子。 我们已经表明，这些鼻溶剂可以在临床前模型中延迟OA。我们还表明 用Losartan（TGF-β1Blocker）阻断纤维化可以通过促进再生来改善软骨修复 透明软骨，同时减少纤维球纤维的量。那我们假设管理 鼻溶剂和/或抗纤维化剂将增强BMSC对OA的有益作用。我们建议 在Steadman Clinic（TSC）和Steadman Philippon Research Institute上进行随机临床试验。 （Spri）。该阶段I/II试验将评估Fisetin的安全性和效率（鼻溶剂饮食补充剂）和 Losartan（一种抗纤维化药物），单独或组合使用，用于提高 BMSC治疗膝关节骨关节炎。塞溶菌素（fisetin 1000mg/天，以前是FDA IND 批准的）方案将是每/28天的循环，在BMSC之前和3个月后进行管理 治疗。抗纤维化（Losartan，25mg/天，以前被豁免）将进行30天 在BMSC治疗后立即开始。 OA膝关节将在基线时进行MRI，并在 随着时间的流逝，可以评估软骨形态和结构的变化。患者报告的结果 疼痛和功能将在基线和3、6、12和18个月收集。关节和软骨功能将是 使用基线和18个月的视频运动分析评估。与软骨有关的OA生物标志物 退化，感染和疼痛将在基线和18个月时评估。血液和滑液将 在治疗后的基线，4天和18个月的基线评估，以评估细胞感应的变化和 OA生物标志物。该试验将基于当前主动的OA治疗原生物学临床试验 Spri（利用相同的患者人群和结果评估），证明了我们团队的能力 进行拟议的研究并利用合并试验以有效提供6臂 对改善OA治疗的生物疗法的全面评估。