Facioscapulohumeral dystrophy clinical trial foundations

面肩肱营养不良临床试验基础

• 批准号: 10712153
• 负责人: Stephen J Tapscott
• 金额: $ 70.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-07 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712153
• 关键词: Artificial Intelligence; Biological Markers; Biopsy; Cell Line; Cellular Assay; Characteristics; Clenbuterol; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cohort Studies; Collaborations; D4Z4; Data; Data Set; Development; Disease; Disease Progression; Disease model; Dose; Evaluation; Extracellular Matrix; Facioscapulohumeral; Family; Family suidae; Fatty acid glycerol esters; Foundations; Funding; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Histology; Human; In Vitro; Individual; Inflammation; Longterm Follow-up; Magnetic Resonance Imaging; Mammals; Measurement; Measures; Modeling; Molecular; Molecular Profiling; Muscle; Muscle Cells; Muscular Dystrophies; Myoblasts; Natural History; Needles; Onset of illness; Outcome Measure; Pathology; Pathway interactions; Patient Outcomes Assessments; Patients; Performance; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Pre-Clinical Model; Predictive Value; Readiness; Regulation; Research; Safety; Site; Task Performances; Techniques; Testing; Therapeutic Clinical Trial; Time; Transgenic Organisms; automated analysis; automated segmentation; biomarker validation; clinical care; cohort; design; drug development; early detection biomarkers; efficacy clinical trial; follow-up; gait examination; improved; magnetic resonance imaging biomarker; molecular marker; open label; porcine model; predictive modeling; programs; prospective; rate of change; safety study; secondary outcome; success; targeted treatment; therapeutic development; tool; treadmill; trial design

Summary/Abstract Project 2: Facioscapulohumeral Clinical Trial Foundations Project 2 will establish facioscapulohumeral dystrophy (FSHD) clinical trial foundations. The success in identifying the molecular and genetic mechanisms of FSHD provides a strong basis for drug development and therapeutic clinical trials. A major barrier to drug development is lack of validated biomarkers for early phase and proof of concept gene targeted therapies. In addition, the lack of understanding progression over time limits trial design and clinical care. In our prior Wellstone we showed quantitative fat fraction on MRI can demonstrate progression over 1-2 years; with certain MRI features (STIR+, and intermediate fatty involvement at baseline) predicting faster progression rates. The same MRI features also correlated with a basket of FSHD related genes in needle muscle biopsies – including genes related to DUX4 expression, inflammation, and extracellular matrix. Here we plan to extend and expand our foundations for clinical trial preparedness. The broad and long-term goals of this study are to further refine our understanding of MRI as a biomarker by applying artificial intelligence driven automated segmentation and analyses to existing and new long-term follow up data, apply our MRI and molecular biomarkers to a safety and tolerability study of clenbuterol, a drug we identified as inhibiting DUX4 in patient derived cell assays, and using these tools to validate and phenotype a new large mammal model of FSHD type1. This will be accomplished by (Aim 1) extension of the longitudinal clinical study cohorts of FSHD to additional long-term functional and MRI assessments with improved MRI analytic techniques; (Aim 2) perform a prospective 6-month open label multiple ascending dose safety and tolerability study of clenbuterol in FSHD with secondary outcome measures that include functional studies, MRI characteristics, muscle histology, and the muscle molecular signature; and (Aim 3) validating a porcine model of FSHD1 and generating bioresources to support the development of pigs as preclinical models for FSHD. Together, these aims will (1) further validate, refine, and extend clinical, MRI, and molecular measurements of disease activity and progression in FSHD muscles to allow for a better understanding of FSHD progression and the size of change that will be clinically meaningful and ; (2) determine whether clenbuterol is safe and tolerated, and which dose may show preliminary signs of efficacy to support a future phase II clinical trial; and (3) validate a new porcine model of FSHD1 using these functional, MRI, and molecular measurements. The significance of this study is that it will strengthen and extend the foundations for clinical trial design and help hasten therapeutic development for FSHD.

摘要/摘要 项目2：面肩肩关节临床试验基础 项目2将建立面部肩关节骨营养不良(FSHD)临床试验基础。在中国取得的成功 明确FSHD的分子和遗传机制为药物的开发和治疗提供了有力的基础 治疗性临床试验。药物开发的一个主要障碍是缺乏经过验证的早期生物标志物。 以及概念基因靶向治疗的证据。此外，缺乏了解会随着时间的推移而进步 限制试验设计和临床护理。在我们之前的Wellstone中，我们在MRI上显示了定量脂肪分数 进展超过1-2年；有一定的MRI特征(STIR+，中度脂肪受累 在基线)预测更快的进展速度。同样的MRI特征也与一篮子FSHD相关 针刺肌肉活检中的相关基因-包括与DUX4表达、炎症和 细胞外基质。在这里，我们计划扩大和扩大我们的临床试验准备基础。这个 这项研究的广泛和长期目标是通过以下方式进一步完善我们对MRI作为生物标记物的理解 将人工智能驱动的自动分割和分析应用于现有和新的长期 追踪数据，将我们的MRI和分子生物标记物应用于克伦特罗的安全性和耐受性研究 我们确定在患者来源的细胞检测中抑制DUX4，并使用这些工具来验证和表型 一种新的FSHD大型哺乳动物模型1。这将通过(目标1)纵向延伸来实现 FSHD的临床研究队列通过改进的MRI进行额外的长期功能和MRI评估 分析技术；(目标2)进行前瞻性的6个月开放标签多次递增剂量安全性和 包括功能研究、磁共振成像在内的二次结果评估方法研究克伦特罗在FSHD中的耐受性 特征、肌肉组织学和肌肉分子特征；以及(目标3)验证猪模型 并产生生物资源以支持猪作为FSHD的临床前模型的发展。 总之，这些目标将(1)进一步验证、改进和扩展临床、核磁共振和分子测量 FSHD肌肉中的疾病活动和进展允许更好地了解FSHD的进展 以及将具有临床意义的变化的大小；以及(2)确定克伦特罗是否安全和 耐受性，以及哪个剂量可能显示出初步疗效迹象，以支持未来的第二阶段临床试验；以及 (3)使用这些功能、MRI和分子测量来验证新的猪FSHD1模型。这个 本研究的意义在于，它将加强和延伸临床试验设计的基础，并有助于 加快FSHD的治疗发展。