MR Monitoring of PTC124 Treatment in DMD

描述（由申请人提供）：PTC124治疗DMD的MR监测。该应用程序解决了广泛的挑战领域（03）生物标志物的发现和验证以及特定的挑战主题；03-AR 104：成像生物标志物。DMD是最具破坏性的遗传相关神经肌肉疾病之一，其特征是缺乏肌营养不良蛋白，导致进行性肌肉无力，丧失行走能力和过早死亡。尽管肌肉萎缩症患者预后不良，但缺乏治疗干预措施，临床试验的结果测量仅限于肌肉功能和生活质量的测量，肌肉分解的血清生物标志物和侵入性肌肉活检。需要对肌肉结构和成分变化敏感的其他非侵入性生物标志物，以促进从临床前研究到临床试验的有希望的新干预措施的快速转化。因此，本研究的目的是验证磁共振成像（MRI）和波谱（MRS）在监测DMD儿童疾病进展和对治疗干预的反应方面的潜力。拟议的研究利用了最近启动的PTC124 2a期扩展研究，该研究涉及长期给药（96周）PTC124，一种新型停止密码子抑制药物。高达15%的患有DMD的男孩不能产生肌营养不良蛋白，因为在肌营养不良蛋白mRNA中产生过早停止密码子的点突变。停止密码子抑制药物，如PTC124，允许停止密码子被忽略，整个肌营养不良蛋白被翻译。1期和2a期试验表明，口服生物可利用PTC124具有良好的耐受性，可诱导全长肌营养不良蛋白产生的部分恢复，并降低mdx小鼠和无意义突变介导的DMD男孩的肌肉脆性。在拟议的研究中，我们将招募20名参加2a期扩展研究的流动男孩，以确定MRI/MRS监测PTC124治疗对骨骼肌的短期和长期影响的能力。在PTC124治疗开始前和开始后的多个时间点，将在下肢肌肉进行肌肉损伤/炎症、肌肉收缩组织和肌内脂质积累的磁共振测量。一组目前未接受PTC124治疗的男孩（n=20）将在同一时间点进行测试，并作为对照。最终，影像学数据将与疾病进展/消退的功能和组织学结果指标相关联。这项研究提供了一个前所未有的机会来验证MRI/MRS在监测针对DMD男孩肌营养不良蛋白生产恢复的治疗干预效果方面的潜力。我们预计，在本提案中开发和验证的MR技术将适用于广泛的肌肉萎缩症的临床试验。佛罗里达大学和宾夕法尼亚大学为当地和地区经济做出了巨大贡献。2008年，佛罗里达大学创造了2525个工作岗位，最近的研究表明，佛罗里达大学每年为佛罗里达经济贡献近60亿美元。该大学在其主校区直接雇用了约34,000人，并通过佛罗里达大学组织，如食品和农业科学研究所，负责在全州创造74,894个工作岗位。2008年，宾夕法尼亚大学医学院为该地区创造了37,000个工作岗位和54亿美元的经济活动，该地区训练有素的劳动力为840个宾夕法尼亚大学的研究职位提供了24,600多份申请。目前的提议将在两个不同的州创造或保留至少14个工作岗位，所有基础设施都已到位，可以立即启动该项目。

DESCRIPTION (provided by applicant): MR monitoring of PTC124 treatment in DMD. This application addresses broad challenge area (03) Biomarkers Discovery and Validation and Specific Challenge Topic; 03-AR 104: Imaging Biomarkers. DMD is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis for patients with muscular dystrophy, therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function and quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Additional noninvasive biomarkers that are sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. Therefore, the objective of this study is to validate the potential of magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and the response to therapeutic interventions in children with DMD. The proposed study capitalizes on the recently initiated PTC124 phase 2a extension study, which involves the long-term administration (96 weeks) of PTC124, a novel stop codon suppression drug. Up to 15% of boys with DMD fail to make dystrophin because of a point mutation that creates a premature stop codon in the dystrophin mRNA. Stop codon suppression drugs, such as PTC124, allow the stop codon to be ignored and the entire dystrophin to be translated. Phase 1 and 2a testing have shown that orally bioavailable PTC124 is well tolerated, induces partial restoration of full-length dystrophin production and reduces muscle fragility in both mdx mice and boys with nonsense-mutation-mediated DMD. In the proposed study we will enroll 20 ambulatory boys participating in the phase 2a extension study to determine the ability of MRI/MRS to monitor the short and long term effect of PTC124 treatment on skeletal muscle. Magnetic resonance measurements of muscle damage/inflammation, muscle contractile tissue and intramuscular lipid accumulation will be performed in the lower extremity muscles prior to, and at multiple time points following initiation of PTC124 treatment. A subgroup of boys (n=20) not currently treated with PTC124 will be tested at the same time points and serve as controls. Ultimately, imaging data will be correlated with functional and histological outcome measures of disease progression/regression. This study provides an unprecedented opportunity to validate the potential of MRI/MRS to monitor the efficacy of therapeutic interventions targeting the restoration of dystrophin production in boys with DMD. We anticipate that the MR techniques developed and validated in this proposal will be suitable for clinical trials in a wide range of muscular dystrophies. The University of Florida and the University of Pennsylvania contribute substantially to the local and regional economy. In 2008, UF created 2,525 jobs and recent studies have shown that UF contributes nearly $6 billion annually to Florida's economy. The university employs about 34,000 people directly on its main campus and via UF organizations, such as the Institute of Food and Agricultural Sciences, is responsible for the creation of 74,894 jobs statewide. Penn Medicine created about 37,000 jobs and $5.4 billion in regional economic activity in 2008, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain at least 14 jobs across two different states and all the infrastructure is in place to immediately initiate the project. Public Health Relevance: The goal of this project is to develop a way to observe whether or not new therapies are effective in correcting the disease process in muscles of boys with Duchenne muscular dystrophy (DMD) without the need to take muscle biopsies. To date, the only relatively noninvasive method of monitoring the disease process is unreliable and measures blood levels of creatine kinase. We have evidence in mouse models of both DMD and limb girdle muscular dystrophy, that magnetic resonance imaging can be used to track disease progression and monitor the efficacy of therapeutic interventions. We will extend our past mouse studies to boys who are participating in the Phase 2a clinical trial of PTC124, a promising new drug for DMD boys with premature stop codons. The availability of a reliable, nondestructive monitoring method that can be routinely and repeatedly implemented in patients will greatly benefit clinical trials in muscle diseases.