Identifying Genetic Modifiers and Potential Therapeutics for NGLY1 Deficiency

项目摘要 罕见病影响了3000万美国人，但只有10%的罕见病有有效的治疗方法。NGLY1 缺乏症是一种罕见的疾病，没有有效的治疗方法，个体表现出无泪，发育迟缓， 运动障碍和癫痫NGLY 1缺陷是由NGLY 1的功能缺失突变引起的， 从糖蛋白上切割N-连接聚糖的去糖基化酶。这项提案的目标是开发潜力 通过鉴定可作为治疗靶点的遗传修饰剂来治疗NGLY 1缺陷 并通过进行无偏的小分子筛选。NGLY 1中存在大范围的表型变异 缺乏，表明遗传背景的影响。表型异质性的基础基因 NGLY 1缺乏是未知的，但他们可能提供深入了解疾病机制，并提供治疗 靶向疾病修饰途径的途径。Chow实验室最近进行了一项遗传修饰筛选， 使用遗传多样性果蝇基因组构建NGLY 1缺陷的黑腹果蝇模型 参考面板（DGRP）。一些DGRP系在损失NGLY 1后是完全存活的，而其他DGRP系在损失NGLY 1后是完全存活的。 百分之百致命全基因组关联分析确定了61个似乎影响致死率的基因。目标1 这项建议会跟进这些候选基因修饰物。在失去时赋予保护作用的基因 的NGLY 1是特别感兴趣的，因为它们可以作为NGLY 1缺乏症的潜在治疗途径。 该提案的目的2是进行小分子筛选，以获得在NGLY 1中挽救致死性的化合物。 果蝇模型。该屏幕将集中在FDA批准的化合物，以努力简化 我们的苍蝇模型的研究结果对人类状况的适用性。目标2还涉及药物基因组学 罕见疾病的挑战。药物反应的个体间差异在人群中很常见， 一些个体对治疗反应良好，而一些个体具有不良药物反应。DGRP 将用于研究遗传背景如何影响治疗效果，并确定基因变异 在为NGLY 1缺乏人群开发安全有效的治疗方法时需要考虑这一点。 犹他州大学是这个项目的理想场所。赞助商，克莱门特周博士，开发了多个 果蝇疾病模型，并在使用遗传变异来识别疾病修饰基因方面具有专业知识。的 人类遗传学系培养了一个强大的博士后培训环境，并由多个世界 著名的遗传学专家，他们中的许多人都与果蝇有关。共同发起人兰德尔·彼得森博士 在药物开发领域取得了成功，并在指导成功的博士后方面有着良好的记录。的 本建议中概述的培训将使受训者能够发展他们的果蝇技能，学习新的统计知识， 技术，成为小分子药物筛选的知识，生产研究直接适用于 人类健康，并发展成为独立研究科学家的技能。

Project Summary Rare diseases impact 30 million Americans yet only 10% of rare diseases have an effective treatment. NGLY1 deficiency is one rare disease with no effective treatment and individuals display alacrima, developmental delay, movement disorders, and seizures. NGLY1 deficiency is caused by loss-of-function mutations in NGLY1, a deglycosylase that cleaves N-linked glycans from glycoproteins. The goal of this proposal is to develop potential treatment options for NGLY1 deficiency by identifying genetic modifiers that may serve as therapeutic targets and by conducting an unbiased small molecule screen. There is a large range of phenotypic variability in NGLY1 deficiency, suggesting an effect of genetic background. The genes that underlie phenotypic heterogeneity in NGLY1 deficiency are unknown, yet they may offer insights into disease mechanisms and provide therapeutic avenues to target disease modifying pathways. The Chow lab recently performed a genetic modifier screen in a Drosophila melanogaster model of NGLY1 deficiency using the genetically diverse Drosophila Genetic Reference Panel (DGRP). Some DGRP lines were completely viable upon loss of NGLY1, while others were 100% lethal. A genome wide association analysis identified 61 genes that appeared to impact lethality. Aim 1 of this proposal will follow up on these candidate genetic modifiers. Genes that confer a protective effect upon loss of NGLY1 are of particular interest as they may serve as a potential treatment avenue for NGLY1 deficiency. Aim 2 of this proposal is to conduct a small molecule screen for compounds that rescue lethality in an NGLY1 deficiency Drosophila model. The screen will focus on FDA approved compounds in efforts to streamline the applicability of findings from our fly model to the human condition. Aim 2 also addresses pharmacogenomics challenges in rare diseases. Interindividual variation in drug response is common in the human population, with some individuals responding well to treatment and some individuals having adverse drug responses. The DGRP will be utilized to investigate how genetic background impacts treatment efficacy and to identify gene variants that need to be considered when developing safe and effective treatments for the NGLY1 deficiency population. The University of Utah is an ideal setting for this project. The sponsor, Dr. Clement Chow, has developed multiple Drosophila disease models and has expertise in using genetic variation to identify disease modifying genes. The Department of Human Genetics fosters a strong postdoctoral training environment and consists of multiple world renowned genetics experts, many of whom work with Drosophila. The co-sponsor, Dr. Randall Peterson, is highly successful in the drug development field and has a strong track record of mentoring successful postdocs. The training outlined in this proposal will allow the trainee to develop their Drosophila skills, learn new statistical techniques, become knowledgeable in small molecule drug screening, produce research directly applicable to human health, and develop the skills to become an independent research scientist.