Measuring and Understanding Light Sensitivity in Erythropoietic Protoporphyria

项目概要/摘要 红细胞生成性原卟啉症（EPP）是由血红素生物合成的最后一种酶的致病性变体引起的， 其产生终生的、疼痛的皮肤对光敏感性。在EPP中，光敏分子 原卟啉IX（PPIX）在红细胞中积累，其次在血浆和肝脏中积累。除了 光敏性，EPP可导致贫血，胆结石和慢性肝病，2-5%的患者发展为 快速进行性胆汁淤积性肝衰竭，如果不进行肝移植是致命的。批准新 由于缺乏定量的临床试验终点，EPP的治疗受到很大阻碍。而 美国食品和药物管理局最近批准了一种有助于预防EPP相关疾病的治疗方法。 光敏性，没有疾病修饰疗法可用于EPP。本研究的目的是开发 方法来定量测量光敏感性在EPP和了解遗传基础的差异， 患者的光敏感性。光敏感性将通过光剂量测定， 经皮PPIX荧光测定法和每日文本症状调查。光照差异的遗传基础 患者的敏感性将通过进行全外显子组测序和基因分型来表征 在具有相同FECH基因型且光敏感性和/或 PPIX等级。首先，将在大型数据集中开发的多基因风险评分应用于遗传数据 在这个特定的患者群体中。接下来，将在外显子组中识别疾病修饰编码变体。 序列，然后进行体外验证。该项目可以导致（1）预测和预防的方法 EPP的光敏性，从而改善生活质量，（2）临床试验的定量终点， 新疗法的批准，以及（3）更好地了解EPP中的光敏感性调节剂， 可能会带来新的治疗方法这项研究将由医学讲师Amy Dickey博士进行 在哈佛医学院和马萨诸塞州总医院。她将接受一流的统计学培训， 流行病学、临床试验设计和遗传分析。此外，她将特别指导博士。 遗传和环境流行病学专家大卫·克里斯蒂安尼与马克·弗莱明博士共同指导， 血红素代谢和罕见病基因分析专家。她将在一个- 迪基博士的目标是成为一个著名的学术中心，并为她提供所有所需的资源。 以患者为导向的卟啉症研究的医生兼科学家。这个K23奖项将为她提供培训， 导师实现独立，并申请她的第一个R 01。

PROJECT SUMMARY / ABSTRACT Erythropoietic protoporphyria (EPP) is caused by pathogenic variants of the last enzyme of heme biosynthesis, which produces life-long, painful cutaneous sensitivity to light. In EPP, the light-sensitive molecule protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in the plasma and the liver. In addition to photosensitivity, EPP can result in anemia, gallstones, and chronic liver disease, and 2-5% patients develop rapidly progressive cholestatic liver failure that is fatal without liver transplantation. The approval of new therapeutics in EPP has been greatly hindered by the lack of quantitative clinical trial endpoints. While the Food and Drug Administration recently approved one therapy that helps to prevent EPP-related photosensitivity, no disease-modifying therapy is available for EPP. The objective of this study is to develop methods to quantitatively measure light sensitivity in EPP and to understand the genetic basis for differences in light sensitivity among patients. Light sensitivity will be measured by the combination of light dosimetry, transcutaneous PPIX fluorometry, and daily text symptom surveys. The genetic basis for differences in light sensitivity among patients will be characterized by performing whole exome sequencing and a genotyping array in EPP patients possessing the same FECH genotype and large discordances in light sensitivity and/or PPIX level. First, polygenic risk scores that were developed in large datasets will be applied to the genetic data of this selected patient population. Next, disease-modifying coding variants will be identified in the exome sequences, followed by in vitro validation. This project could lead to (1) methods to predict and prevent photosensitivity in EPP thus improving quality of life, (2) quantitative endpoints for clinical trials facilitating the approval of new therapies, and (3) a better understanding of the modulators of light sensitivity in EPP, which could lead to novel therapeutics. This research will be performed by Dr. Amy Dickey, an Instructor of Medicine at Harvard Medical School and Massachusetts General Hospital. She will receive first-rate training in statistics, epidemiology, clinical trial design, and genetic analysis. Furthermore, she will be exceptionally mentored by Dr. David Christiani, an expert in genetic and environmental epidemiology, and co-mentored by Dr. Mark Fleming, an expert in heme metabolism and rare disease genetic analysis. She will perform her research in a world- renowned academic center with all required resources available to her. Dr. Dickey's goal is to become a physician-scientist in patient-oriented porphyria research. This K23 award will provide her with the training and mentorship to achieve independence and apply for her first R01.