Clinical Trial Readiness for the Dystroglycanopathies

该项目的目的是收集信息并创建计划和开展α-肌营养不良蛋白聚糖糖基化缺陷患者临床试验所需的基础设施。这些患者患有肌营养不良，有或没有多系统受累（肌营养不良聚糖病）。到目前为止，已知六种基因（P0 MT 1、P0 MT 2、P0 MGnTI、FKTN、FKRP和LARGE）中的突变导致肌营养不良聚糖病。有几种临床亚型，并且这些具有重叠的表型。由于临床严重程度的广泛性，肌营养不良症人群在考虑治疗试验方面提出了特殊的挑战。此外，在某些亚型中观察到的认知障碍限制了患者配合测试的能力。 在目标1中，我们将招募疑似或确诊为肌营养不良聚糖病的患者，并使用历史信息、标准化功能测试和肌肉超声来确定其临床表型。与Core B合作，我们将评估肌肉活检，确定培养成纤维细胞中患者的α-肌营养不良蛋白聚糖糖基化状态，并确定其基因型。在目标2中，我们将使用一系列潜在的临床试验结局指标纵向随访肌营养不良聚糖病患者。这将为我们提供自然史信息，并确定用于治疗试验的最佳结局指标。在目标3中，我们将使用目标1和2中收集的数据指导试验设计，为拟议的皮质类固醇临床试验开发基础设施。轶事和病例报告表明皮质类固醇对肌营养不良症患者有益。在本提案中，我们将开发患者队列、结果标记和基础设施来验证这一假设。我们希望这三个目标的结果将使我们准备好评估这些罕见形式的肌营养不良症的新治疗方法。

The purpose of this project is to gather the information and create the infrastructure needed to plan and carry out clinical trials for patients with deficient glycosylation of alpha-dystroglycan. These patients have muscular dystrophy, with or without multisystem involvement (the dystroglycanopathies). Thus far, mutafions in six genes (POMTl, P0MT2, POMGnTI, FKTN, FKRP, and LARGE) are known to result in dystroglycanopathies. There are several clinical subtypes, and these have overiapping phenotypes. The dystroglycanopathy population poses special challenges in thinking about treatment trials due to the wide range in clinical severity. In addition, the cognitive impairment seen in some of the subtypes limits patients' ability to cooperate with testing. In Aim 1, we will recruit patients with suspected or proven dystroglycanopathies and define their clinical phenotypes using historical information, standardized functional tests, and muscle ultrasound. In cooperation with Core B, we will evaluate muscle biopsies, define patients' alpha-dystroglycan glycosylation status in cultured fibroblasts, and determine their genotype. In Aim 2, we will follow patients with dystroglycanopathy longitudinally using a battery of potential clinical trial outcome measures. This will provide us with natural history information and determine optimal outcome measures for use in therapeutic trials. In Aim 3, we will develop the infrastructure for a proposed clinical trial of corticosteroids, using the data collected in Aims 1 and 2 to guide trial design. Anecdotes and case reports suggest corticosteroids are beneficial in patients with the dystroglycanopathies. In this proposal, we will develop the patient cohort, outcome markers and infrastructure to test this hypothesis. We expect that the results of these three aims will prepare us to evaluate novel treatments for these rare forms of muscular dystrophy as they become available.