MR Monitoring of PTC124 Treatment in DMD

描述(申请人提供)：DMD患者PTC124治疗的MR监测。本申请涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题；03-AR 104：成像生物标记物。DMD是最具破坏性的遗传相关神经肌肉疾病之一，其特征是Dstrophin的缺失，导致进行性肌肉无力、行走能力丧失和过早死亡。尽管肌营养不良患者的预后很差，但一直缺乏治疗干预措施，临床试验的结果衡量标准仅限于肌肉功能和生活质量的测量、肌肉破裂的血清生物标记物和侵入性肌肉活检。需要更多对肌肉结构和成分变化敏感的非侵入性生物标志物，以促进有希望的新干预措施从临床前研究快速转化为临床试验。因此，这项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。这项拟议的研究利用了最近启动的PTC124阶段2a扩展研究，该研究涉及长期服用(96周)PTC124，一种新型终止密码子抑制药物。高达15%的患有DMD的男孩无法生成dystrophin，因为点突变在dystrophin mRNA中产生了一个过早的终止密码子。终止密码子抑制药物，如PTC124，允许忽略终止密码子，并翻译整个dystrophin。1期和2a期试验表明，口服生物利用型PTC124具有良好的耐受性，可以部分恢复全长Dstrophin的产生，并降低MDX小鼠和患有无义突变介导的DMD的男孩的肌肉脆性。在这项拟议的研究中，我们将招募20名活动男童参加2a期扩展研究，以确定MRI/MRS监测PTC124治疗对骨骼肌的短期和长期效果的能力。在PTC124治疗开始之前和之后的多个时间点，将对腿部肌肉进行肌肉损伤/炎症、肌肉收缩组织和肌肉内脂肪堆积的磁共振测量。目前没有接受PTC124治疗的一组男孩(n=20)将在相同的时间点进行测试，并作为对照。最终，成像数据将与疾病进展/消退的功能和组织结果指标相关联。这项研究提供了一个前所未有的机会来验证MRI/MRS在监测针对恢复DMD男孩的Dstrophin产生的治疗干预的有效性的潜力。我们预计，在这项建议中开发和验证的磁共振技术将适用于广泛的肌肉营养不良症的临床试验。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重大贡献。2008年，UF创造了2525个就业机会，最近的研究表明，UF每年为佛罗里达州的经济贡献近60亿美元。该大学直接在主校区雇佣了约3.4万人，并通过UF组织，如食品和农业科学研究所，负责在全州范围内创造74,894个就业机会。宾夕法尼亚大学医学院在2008年创造了约3.7万个就业机会和54亿美元的区域经济活动，该地区训练有素的劳动力仅为840个宾夕法尼亚大学员工研究职位空缺就产生了超过24600份申请。目前的提案将在两个不同的州创造或保留至少14个就业机会，所有基础设施都已到位，可以立即启动该项目。 公共卫生相关性：该项目的目标是开发一种方法来观察新的治疗方法是否有效地纠正了患有杜氏肌营养不良症(DMD)的男孩的肌肉疾病过程，而不需要进行肌肉活检。到目前为止，唯一一种相对非侵入性的监测疾病过程的方法是不可靠的，它测量血液中肌酸激酶的水平。我们在DMD和肢体带状肌营养不良的小鼠模型中都有证据表明，磁共振成像可以用于跟踪疾病进展和监测治疗干预的效果。我们将把过去的小鼠研究扩展到参加PTC124 2a期临床试验的男孩，PTC124是一种很有前途的新药，用于治疗患有过早终止密码子的DMD男孩。一种可靠的、非破坏性的监测方法的可用性，可以在患者身上常规和重复实施，将极大地促进肌肉疾病的临床试验。

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.