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，导致软骨损伤、疼痛和丧失