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: 10468269
• 负责人: Johnny Huard
• 金额: $ 62.11万
• 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/10468269
• 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; antifibrotic treatment; 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; 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,会导致软骨损伤、疼痛和关节功能丧失。 功能。虽然许多治疗 OA 的干细胞疗法正在研究中，但目前尚无 FDA 批准用于治疗 OA 的干细胞疗法。 改变病程。在许多可能适用于 OA 的成体干细胞类型中，骨髓 来自骨髓抽吸浓缩物 (BMC) 的干细胞 (BMSC) 最具临床可转化性（并且 已经在临床使用），因为它们可以使用微创技术收获，并且不需要 体外扩增。然而，BMSC 治疗 OA 的疗效具有巨大的潜力。这 BMC 中的衰老细胞数量随着年龄和 OA 的增加而增加，这些细胞释放促炎物质 细胞因子/趋化因子、蛋白酶和其他衰老相关的分泌表型 (SASP) 损害干细胞功能并可能导致 OA 的发生/进展。柯克兰博士的实验室（合作 研究人员）已经鉴定出能够特异性杀死衰老细胞、消除全身 SASP 因子的化合物。 我们已经在临床前模型中证明这些抗衰老药物可以延迟 OA。我们还表明 用氯沙坦（一种 TGF-β1 阻滞剂）阻断纤维化可以通过促进软骨再生来改善软骨修复 透明软骨同时减少纤维软骨的量。因此，我们假设管理 抗衰老剂和/或抗纤维化剂将增强 BMSC 治疗 OA 的有益效果。我们建议 在 Steadman Clinic (TSC) 和 Steadman Philippon 研究所进行的一项随机临床试验 （SPRI）。该 I/II 期试验将评估 Fisetin（一种 senolytic 膳食补充剂）的安全性和功效，以及 氯沙坦（一种抗纤维化药物），单独或联合使用，用于改善以下疾病的临床疗效 BMSCs 治疗膝骨关节炎。 senolytic（Fisetin 1000mg/天，之前已获得 FDA IND 批准的）方案将是 2 天/28 天休息的周期，在 BMSC 之前和之后 3 个月进行 治疗。抗纤维化药物（氯沙坦，25mg/天，之前已获得 IND 豁免）将持续 30 天 BMSC 治疗后立即开始。 OA 膝关节将在基线和术后 18 个月接受 MRI 检查 治疗以评估软骨形态和结构随时间的变化。患者报告的结果 将在基线以及 3、6、12 和 18 个月时收集疼痛和功能。关节和软骨功能将 在基线和 18 个月时使用视频运动分析进行评估。与软骨相关的 OA 生物标志物 将在基线和 18 个月时评估变性、炎症和疼痛。血液和滑液会 在基线、治疗后 4 天和 18 个月进行评估，以评估细胞衰老的变化和 OA 生物标志物。该试验将建立在目前正在进行的骨关节炎治疗骨生物制剂临床试验的基础上 SPRI（利用相同的患者群体和结果评估），展示了我们团队的能力 进行拟议的研究，并利用联合试验有效地提供 6 臂， 对改善 OA 治疗的生物疗法进行综合评估。