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

翻译后摘要：骨关节炎（OA）是一种渐进性关节疾病，导致软骨损伤，疼痛和损失的 功能虽然许多用于OA的干细胞疗法正在研究中，但目前没有一种被FDA批准用于 改变疾病的进程。在许多可能适用于OA的成体干细胞类型中，骨髓干细胞是最常见的干细胞类型。 来自骨髓抽吸浓缩物（BMC）的干细胞（BMSC）是临床上最可转化的（并且 已经在临床上使用），因为它们可以使用微创技术来获取，并且不需要 体外扩增然而，有显着的潜力，提高疗效的BMSC治疗OA。的 BMC中衰老细胞的数量随着年龄和OA而增加，这些细胞释放促炎性因子 细胞因子/趋化因子、蛋白酶和其他衰老相关分泌表型（SASP）， 损害干细胞功能并可能导致OA发展/进展。柯克兰博士的实验室（合作） 研究人员）已经鉴定出特异性杀死衰老细胞的化合物，消除系统性SASP因子。 我们已经证明，这些衰老清除剂可以在临床前模型中延迟OA。我们还表明， 用Losartan（一种TGF-β 1阻断剂）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， 衰老清除剂和/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）.这项I/II期试验将评估非瑟酮（一种衰老清除膳食补充剂）的安全性和有效性， 氯沙坦（一种抗纤维化药物），单独或联合使用，用于改善 骨髓间充质干细胞治疗膝关节骨关节炎。Senolytic（非瑟酮1000毫克/天，以前FDA IND 批准的）方案将是2天/28天的周期，在BMSC之前和之后3个月施用 治疗将给予抗纤维化药物（氯沙坦，25 mg/天，之前IND豁免）30天 在BMSC处理后立即开始。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。患者报告的结局 将在基线和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个月时评估退化、炎症和疼痛。血液和滑液 在基线、治疗后4天和18个月进行评价，以评估细胞衰老的变化， 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的生物制品临床试验基础上， SPRI（使用相同的患者人群和结局评估），证明了我们团队的能力 为了进行所提出的研究并利用组合试验来有效地提供6组， 全面评估生物疗法对改善OA治疗的作用。

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.