Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

肌营养不良症的磁共振成像和生物标志物

• 批准号: 10466943
• 负责人: KRISTA H VANDENBORNE
• 金额: $ 123.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10466943
• 关键词: 9 year old; Abdomen; Address; Age; Alleles; Becker Muscular Dystrophy; Biological Markers; Biopsy; Cause of Death; Chest wall structure; Cine Magnetic Resonance Imaging; Clinical Trials; Clinical Trials Design; Clinical assessments; Communities; Data; Disease; Disease Progression; Disease model; Duchenne muscular dystrophy; Dystrophin; Enrollment; Europe; Exhibits; Fatty acid glycerol esters; Funding; Future; Gene Delivery; Genes; Genetic; Goals; Histologic; Image; Impairment; Individual; Infiltration; Inflammation; International; Leg; Lower Extremity; Magnetic Resonance Imaging; Measures; Molecular; Monitor; Motor; Multi-Institutional Clinical Trial; Multicenter Studies; Muscle; Muscle Weakness; Muscular Atrophy; Muscular Dystrophies; Mutation; Natural History; Outcome Measure; Patients; Pelvic Girdle; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Production; Protocols documentation; Reproducibility; Research; Research Design; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Respiratory physiology; Site; Technology; Testing; Upper Extremity; Wasting Syndrome; Work; advanced disease; arm; arm function; base; biomarker development; chromosome X loss; cohort; curative treatments; data sharing; exon skipping; experience; imaging biomarker; in vivo monitoring; magnetic resonance imaging biomarker; next generation; novel; predictive marker; primary endpoint; pulmonary function; respiratory; response; restoration; secondary endpoint; therapeutic development; whole body imaging

Project Summary The proposed research is for the second competitive renewal of a long-term project to develop imaging biomarkers for Duchenne muscular dystrophy (DMD). Noninvasive outcome measures that provide unbiased patient assessments and reliably evaluate drug responses in clinical trials are essential to develop curative therapies for muscular dystrophies. In the previous funding cycles, we developed and validated lower extremity quantitative magnetic resonance imaging (qMR) biomarkers for ambulatory patients with DMD and modeled the disease trajectory in upper and lower extremity muscles. These qMR biomarkers are now used as primary and secondary endpoints in a number of international clinical trials. In this application one major objective is to extend our DMD work by focusing on older DMD patients with advanced disease progression. More than 50% of the DMD population is nonambulant, yet there are few outcome measures that permit their inclusion in clinical trials. We propose to 1) develop composite qMR biomarkers using quantitative whole-body imaging and 2) validate novel qMR biomarkers that assess respiratory muscle quality and can predict a decline in respiratory function, a major cause of death in muscular dystrophies. We hypothesize that composite qMR biomarkers–statistical constructs that optimally combine fat fraction measures in multiple muscles–are responsive across a wide range of motor abilities in DMD. We will leverage the large (older) DMD cohort currently enrolled in the ImagingDMD natural history study to test these two new qMR biomarkers for advanced disease stages. We also propose to extend our biomarker development work to patients with Becker muscular dystrophy (BMD), the milder allelic form of the disease. Breakthroughs in gene delivery and exon skipping technology have resulted in production of truncated dystrophin in variable amounts, effectively converting the DMD phenotype into BMD. These therapeutic developments are expected to change the landscape for the next generation of DMD patients. Thus, to assist future trials targeting dystrophin restoration, we will examine the critical relationship between dystrophin expression, mutation site and qMR biomarkers of muscle quality in BMD patients, setting the stage for informed in vivo monitoring of dystrophin rescue across muscles. This project addresses critical barriers in therapeutic development and provides the potential for a paradigm shift in clinical trial design in DBMD. In addition, this project will help inform future molecular based therapies and will address a missing piece in translational gene restoration in DMD. All natural history data are shared with the community.

项目摘要 拟议的研究是针对发展成像的长期项目的第二个竞争性续订 Duchenne肌肉营养不良（DMD）的生物标志物。无创的结果指标可提供公正 在临床试验中的患者评估和可靠的评估药物反应对于发展治疗至关重要 肌肉营养不良的疗法。在先前的资金周期中，我们开发并验证了下肢 针对DMD的门诊患者的定量磁共振成像（QMR）生物标志物并建模 上肢和下肢肌肉的疾病轨迹。这些QMR生物标志物现在被用作主要 以及许多国际临床试验中的次要终点。 在此应用中，一个主要目标是通过专注于年长的DMD患者来扩展我们的DMD工作 晚期疾病进展。超过50％的DMD人群是非凸剂的，但很少 允许将其纳入临床试验的结果度量。我们建议1）开发复合QMR 使用定量全身成像和2）验证评估新型QMR生物标志物的生物标志物 呼吸肌肉质量，可以预测呼吸功能的下降，这是肌肉中的主要死亡原因 营养不良。我们假设复合QMR生物标志物 - 统计构建体最佳地结合脂肪 多种肌肉的分数度量 - 在DMD中的各种运动能力中都有响应。我们将 利用当前参加ImagingDMD自然历史研究的大型（较旧的）DMD队列来测试这些 两个新的QMR生物标志物用于晚期疾病阶段。 我们还建议将生物标志物发展工作扩展到贝克尔肌肉营养不良的患者 （BMD），该疾病的米勒等位等位基因形式。基因输送和外显子跳过技术的突破 导致截短肌营养不良蛋白的产生可变量，有效地转换DMD 表型成BMD。预计这些治疗性发展将改变下一个治疗的景观 DMD患者产生。为了协助针对肌营养不良蛋白恢复的未来试验，我们将研究 肌营养不良蛋白表达，突变部位和肌肉QMR生物标志物之间的临界关系 BMD患者的质量，为跨肌肉的肌营养不良蛋白营救的情况奠定了基础。 该项目解决了热开发的关键障碍，并为范式提供了潜力 DBMD中的临床试验设计转移。此外，该项目将有助于告知未来基于分子的疗法 并将解决DMD转化基因恢复中缺失的作品。所有自然历史数据都共享 与社区。