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.

总结/摘要 项目2：面肩肱临床试验基础 项目2将建立面肩肱营养不良（FSHD）临床试验基础。的成功 确定FSHD的分子和遗传机制为药物开发提供了坚实的基础， 治疗性临床试验药物开发的一个主要障碍是缺乏有效的早期生物标志物 和基因靶向疗法的概念验证。此外，由于缺乏理解， 限制了试验设计和临床护理。在我们之前的Wellstone中，我们显示MRI上的定量脂肪分数可以 表现出1-2年的进展;具有某些MRI特征（STIR+和中间脂肪受累 在基线）预测更快的进展速率。同样的MRI特征也与一篮子FSHD相关 针肌肉活检中的相关基因-包括与DUX 4表达，炎症， 细胞外基质在这里，我们计划扩展和扩大我们的临床试验准备的基础。的 这项研究的广泛和长期目标是进一步完善我们对MRI作为生物标志物的理解， 将人工智能驱动的自动化细分和分析应用于现有和新的长期 随访数据，将我们的MRI和分子生物标志物应用于盐酸克伦特罗的安全性和耐受性研究， 我们在患者来源的细胞测定中鉴定为抑制DUX 4，并使用这些工具来验证和表型 一种新的FSHD 1型大型哺乳动物模型。这将通过（目标1）纵向延伸来实现 FSHD的临床研究队列接受额外的长期功能和MRI评估，改善MRI 分析技术;（目的2）进行一项前瞻性6个月开放标签多次递增剂量安全性研究， 克伦特罗在FSHD中的耐受性研究，次要结局指标包括功能研究，MRI 特征、肌肉组织学和肌肉分子标记;以及（目的3）验证猪模型 FSHD 1和生成生物资源，以支持猪作为FSHD临床前模型的开发。 总之，这些目标将（1）进一步验证，完善和扩展临床，MRI和分子测量， FSHD肌肉中的疾病活动和进展，以便更好地了解FSHD进展 以及将具有临床意义的变化的大小;（2）确定克伦特罗是否安全， 耐受性，以及哪种剂量可能显示出初步的疗效迹象，以支持未来的II期临床试验;以及 (3)使用这些功能、MRI和分子测量来验证FSHD 1的新猪模型。的 这项研究的意义在于它将加强和扩展临床试验设计的基础， 加速FSHD的治疗发展。