Clinical Trial Readiness for the Dystroglycanopathies

该项目的目的是收集信息并建立所需的基础设施，以计划和开展针对α-营养不良糖基化缺陷患者的临床试验。这些患者有肌营养不良症，有或没有多系统受累(血糖营养不良症)。到目前为止，已知有6个基因(POMT1、P0MT2、POMGNT1、FKTN、FKRP和LARGE)的突变会导致糖代谢不良。有几个临床亚型，这些亚型有重叠的表型。由于临床严重程度的广泛，糖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，在一些亚型中出现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糖代谢不良的患者，并使用历史信息、标准化功能测试和肌肉超声确定他们的临床表型。与Core B合作，我们将评估肌肉活检，确定患者在培养的成纤维细胞中的α-营养不良糖链糖基化状态，并确定他们的基因。在目标2中，我们将使用一系列潜在的临床试验结果指标对糖营养不良症患者进行纵向跟踪。这将为我们提供自然病史信息，并确定用于治疗试验的最佳结果衡量标准。在目标3中，我们将利用目标1和目标2中收集的数据来指导试验设计，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，糖皮质激素对糖代谢障碍患者是有益的。在这项建议中，我们将开发患者队列、结果标记和基础设施来测试这一假设。我们希望这三个目标的结果将为我们评估这些罕见形式的肌肉营养不良的新治疗方法做好准备，因为它们是可用的。

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, mutations in six genes (POMT1, P0MT2, POMGnT1, FKTN, FKRP, and LARGE) are known to result in dystroglycanopathies. There are several clinical subtypes, and these have overlapping 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.