Thrombotic microangiopathy (TMA) associated MODS after stem cell transplantation

干细胞移植后血栓性微血管病 (TMA) 相关 MODS

• 批准号: 10001993
• 负责人: Sonata Jodele
• 金额: $ 69.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001993
• 关键词: Biological Assay; Biological Markers; Biology; Cells; Cessation of life; Child; Childhood; Clinical; Clinical Markers; Clinical Research; Clinical Trials; Complement; Complement Activation; Complication; Data; Deposition; Diagnosis; Diagnostic; Disease; Disease Marker; Dose; Early Diagnosis; Early Intervention; Early identification; Endothelium; Enrollment; Frequencies; Functional disorder; Future; Gene Expression; Genes; Genetic Complementation Test; Genetic Predisposition to Disease; Genotype; Goals; Hematopoietic Stem Cell Transplantation; Impairment; Individual; Injury; Institution; Interferons; Interleukin-6; Intervention; Literature; Measures; Mediating; Modification; Monitor; Multicenter Trials; Organ; Outcome; Outcome Study; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Preparation; Procedures; Process; Prognostic Marker; Prospective Studies; Proteins; Publishing; Regimen; Research; Resolution; Rest; Risk; Risk stratification; Sampling; Schedule; Screening procedure; Serum; Site; Stem cell transplant; Stress; Syndrome; Testing; Time; Transplant Recipients; Transplantation; Treatment Protocols; Work; base; clinical care; complement pathway; druggable target; experience; gene complementation; genetic variant; hematopoietic cell transplantation; high risk; improved; mortality; new therapeutic target; novel; pharmacokinetics and pharmacodynamics; prophylactic; prospective; randomized placebo controlled trial; screening; transcriptome sequencing; transplant centers; treatment strategy; vascular injury

ABSTRACT Thrombotic microangiopathy (TMA) is an important cause of multi-organ dysfunction syndrome (MODS) and death after hematopoietic cell transplantation (HCT). TMA with MODS occurs in about 11-15% of children after HCT. Mortality with TMA and MODS is about 80%, both in the literature and in our own experience. We have shown that patients with TMA develop MODS through endothelial damage mediated by activation of complement, and have identified complement activation as a poor prognostic marker in TMA. Most importantly, we have shown in a single institution study that complement blockade with eculizumab improves survival. We hypothesize that functional complement studies performed prior to and during HCT will identify patients with increased susceptibility to severe TMA during HCT, and will provide novel pre-transplant screening tools for TMA risk stratification. We also hypothesize that early intervention with eculizumab will double survival in HCT recipients with high risk TMA and MODS, as compared to historical untreated controls. An important goal of this proposal is to identify biological markers that define high-risk patients prior to proceeding to HCT. Our published complement gene sequencing studies indicate that susceptibility to TMA is polygenic, with disease only manifesting under the extreme stress of the HCT process. We found that multiple gene variants modify TMA susceptibility, making pre-transplant genotyping in all patients an impractical approach to identifying high-risk children. In our first specific aim we will test strategies using functional protein-based assays that will allow us to both identify highly susceptible children prior to HCT, and identify the onset of TMA earlier than we currently do, to allow prophylactic and/or earliest possible therapy in future clinical trials. Our first strategy is to test resting state complement activation in serum from 80 children (40 with and 40 without TMA) prior to starting transplant using an endothelial complement deposition assay and a modified Ham’s test, to identify patients at high risk to activate complement during HCT. Our second strategy is to identify endothelial injury occurring after HCT at the earliest possible time by measuring ST2 and NETS formation in 200 children systematically phenotyped for TMA at weekly intervals after HCT. Early identification of endothelial injury will allow intervention before organ damage occurs. In addition, we will perform RNAseq analysis of peripheral blood mononuclear cells from 40 children with TMA at the time of disease, and after resolution of TMA, to identify undescribed dysregulated pathways, and novel potentially druggable targets. In our second aim we will establish an eculizumab treatment regimen that can be generalizable to multiple sites and does not require time-intensive individual pharmacokinetic and pharmacodynamic (PK/PD) monitoring. In preparation for this study we established prospective TMA screening strategies, determined high-risk disease markers, and performed eculizumab PK/PD studies in children receiving HCT. We will treat 21 patients at four major pediatric centers as part of multi-institutional study to establish exportability to other institutions. The regimen is expected to provide satisfactory outcomes for a large majority of children without highly specialized monitoring. These data will be of immediate clinical importance, guiding modification of transplant strategies, TMA screening, and early interventions to improve short and long term transplant outcomes.

摘要 血栓性微血管病（TMA）是多器官功能障碍综合征（MODS）的重要原因， 造血细胞移植（HCT）。HCT后TMA伴MODS发生率约为11-15%。死亡率的 TMA和MODS在文献和我们自己的经验中约为80%。我们已经证明TMA患者 通过补体激活介导的内皮损伤发展MODS，并已鉴定出补体 活化作为TMA的不良预后标记。最重要的是，我们在一项机构研究中表明， 使用依库珠单抗进行补体阻断可提高生存率。我们假设功能性补体研究 在HCT之前和期间，将识别HCT期间对严重TMA易感性增加的患者，并将提供 用于TMA风险分层的新型移植前筛查工具。我们还假设，早期使用依库珠单抗进行干预， 与历史上未治疗的对照相比，在具有高风险TMA和MODS的HCT接受者中将使存活率加倍。一个 该建议的重要目标是在进行HCT之前确定定义高风险患者的生物标志物。 我们已发表的补体基因测序研究表明，TMA的易感性是多基因的， 在HCT过程的极端压力下表现出来。我们发现多种基因变异改变了TMA的易感性， 使得在所有患者中进行移植前基因分型成为识别高危儿童的不切实际的方法。在我们的第一 我们将使用基于功能性蛋白质的测定来测试策略，这将使我们能够识别高度敏感的 儿童HCT之前，并确定TMA的发病早于我们目前做的，以允许预防和/或最早的 在未来的临床试验中可能的治疗。我们的第一个策略是测试80岁以下儿童血清中的静息状态补体激活， 在开始移植前，使用内皮补体沉积试验和 改良Ham试验，以确定HCT期间激活补体的高风险患者。我们的第二个策略是 通过测定200名儿童的ST 2和NETS形成，在HCT后尽早发生内皮损伤 HCT后每周间隔对TMA进行系统表型分析。早期识别内皮损伤将使 在器官损伤发生之前进行干预。此外，我们将对外周血单核细胞进行RNAseq分析。 细胞从40名儿童与TMA在疾病的时间，并在解决TMA，以确定未描述的失调 途径和新的潜在药物靶点。在我们的第二个目标中，我们将建立依库珠单抗治疗方案， 可以推广到多个部位，不需要时间密集的个体药代动力学， 药效学（PK/PD）监测。为了准备这项研究，我们建立了前瞻性TMA筛查策略， 确定高危疾病标志物，并在接受HCT的儿童中进行依库珠单抗PK/PD研究。本公司对待 作为多机构研究的一部分，在四个主要儿科中心对21例患者进行研究，以确定可输出到其他机构。 该方案预计将为大多数没有高度专业化的儿童提供满意的结果。 监测.这些数据将具有直接的临床意义，指导移植策略的修改，TMA 筛查和早期干预，以改善短期和长期移植结果。