Methods to Improve Clinical Trials for A-T

项目总结/摘要：共济失调毛细血管扩张症（A-T）是一种罕见的常染色体隐性遗传病 影响了美国约420人。它的特征是小脑退化， 免疫缺陷、肺部疾病和癌症易感性。A-T在以下方面是复杂且高度可变的： 表现和严重程度，但其可变性的因素尚未完全了解。的 人口规模小，加上广泛的表型变异性，使临床试验具有挑战性。目标 该项目的目的是使A-T的临床试验尽可能有效。我们将利用世界上最大的 A-T临床中心，3个主要的大学医学中心，2个非营利组织和一个家长支持小组，以实现 我们的目标约翰霍普金斯A-T患者队列的规模和多样性使我们处于有利地位， 这项研究需要高度多样化的患者人群。我们假设有可能将 将患者分成严重程度组，这些严重程度组比目前使用的两个广泛组（经典组和 轻度）; A-T引起特定应激和稳态基因的上调; A-T特异性 功能量表将捕获对患者有意义的疾病严重程度的变化。这些假设将 通过以下具体目标进行测试：1。A-T严重程度分层的前瞻性检验，使用 基因型、表型和标准实验室标记。需要更好地定义A-T中的严重性组 A-T疾病严重程度的分层将利用我们非常大的，多样化的 A-T患者队列，并将通过鉴定预测或 定义疾病的严重程度。2.使用RNASeq鉴定与疾病相关的全身性生物标志物 A-T儿童和成人的表型，以帮助进一步将患者分为严重程度组， 用于治疗试验的有用生物标志物。我们认为特异性应激和内稳态的上调 基因将在所有年龄的A-T患者中普遍存在;经典A-T患者的基因表达上调， 与轻度A-T患者相比，使用分类模式， 目标1;社会环境暴露，包括邻里贫困和尼古丁暴露， 改变A-T患者的基因表达差异和DNA甲基化模式。3.验证一个 A-T功能量表用作治疗试验中神经学评分工具的辅助工具。A-T- 具有敏感性的特定功能量表能够捕捉日常生活活动中有意义的变化， 减缓症状发展的药物临床试验。我们将建立一个定量模型， 将提供一种简单，客观的方法来确定疾病的严重程度在A-T，并捕捉有意义的变化， 影响参与和参与活动的职能。

PROJECT SUMMARY / ABSTRACT : Ataxia Telangiectasia (A-T) is a rare autosomal recessive disease affecting ~420 individuals in the United States. It is characterized by cerebellar degeneration, immunodeficiency, pulmonary disease and cancer susceptibility. A-T is complex and highly variable in terms of presentation and severity, but the factors responsible for its variability are not completely understood. The small population size, combined with wide phenotypic variability, have made clinical trials challenging. The goal of this project is to make clinical trials for A-T as effective as possible. We will leverage the world’s largest clinical center for A-T, 3 major university medical centers, 2 non-profits, and a parent support group to achieve our goals. The size and diversity of the Johns Hopkins A-T patient cohort makes us well-positioned to perform this study, which requires a highly diverse patient population. We hypothesize that it is possible to stratify patients into severity groups that are more homogeneous than the two broad groups in use today (classic and mild); that A-T causes upregulation of specific stress and homeostasis genes; and that an A-T specific functional scale will capture changes in disease severity that are meaningful to patients. These hypotheses will be tested through the following Specific Aims: 1. Prospective testing of A-T severity stratification using genotypic, phenotypic and standard laboratory markers. There is a need to better define severity groups in A-T beyond the current state of the art. Stratification of A-T disease severity will utilize our very large, diverse cohort of patients with A-T and will be achieved through identification of a variety of markers that predict or define disease severity. 2. Using RNASeq to identify systemic biomarkers that will correlate with disease phenotypes in children and adults with A-T, to help further stratify patients into severity groups and identify useful biomarkers for therapeutic trials. We propose that upregulation of specific stress and homeostasis genes will be generalizable across all ages of A-T patients; that people with classic A-T will have upregulation of specific inflammatory pathway genes compared to people with mild A-T using the classification schema in Aim 1; and that socio-environmental exposures including neighborhood poverty and nicotine exposure will modify gene expression differences and DNA methylation patterns in people with A-T. 3. Validating a Functional Scale for A-T to be used as an adjunct to neurologic scoring tools in therapeutic trials. An A-T- specific functional scale with sensitivity to capture meaningful changes in activities of daily living is essential to clinical trials of drugs meant to slow the progression of symptoms. We will develop a quantitative model that will provide a simple, objective way to determine disease severity in A-T, and a capture meaningful changes in function that impact engagement and participation in activities.