Identifying Genetic Modifiers and Potential Therapeutics for NGLY1 Deficiency

识别 NGLY1 缺乏症的基因修饰剂和潜在治疗方法

• 批准号: 10407482
• 负责人: Kevin A. Hope
• 金额: $ 2.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407482
• 关键词: Address; Affect; American; Animal Model; Animals; Caregivers; Chemicals; Collection; Complex; Developmental Delay Disorders; Disease; Disease Pathway; Disease model; Drosophila genus; Drosophila melanogaster; Drug Interactions; Drug Screening; Endoplasmic Reticulum; Environment; Enzymes; FDA approved; Fostering; Generations; Genes; Genetic; Genetic Variation; Glucosamine; Glycoproteins; Goals; Health; Heterogeneity; Human; Human Genetics; Individual; Knowledge; Learning; Libraries; Link; Measures; Medical; Mentors; Metabolic; Methods; Modeling; Movement Disorders; Muscle hypotonia; Mutation; N-Glycosylation Site; Oral; Pathogenesis; Pathway interactions; Peptide N-Glycosidase; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Play; Polysaccharides; Population; Postdoctoral Fellow; Quality of life; Rare Diseases; Reporting; Research; Role; Scientist; Seizures; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Treatment Efficacy; Universities; Utah; Whole Organism; Work; career; cost; drug development; drug efficacy; drug repurposing; druggable target; effective therapy; fly; follow-up; gene discovery; genetic variant; genome wide association study; in vivo; insight; inter-individual variation; interest; loss of function mutation; model development; multicatalytic endopeptidase complex; new therapeutic target; novel; novel therapeutics; null mutation; personalized medicine; post-doctoral training; protective effect; receptor; response; screening; skills; small molecule; small molecule libraries; sugar; therapeutic target; tool

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.

项目摘要 罕见疾病影响了3000万美国人，但只有10％的稀有疾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，个人表现出Alacrima，发育延迟， 运动障碍和癫痫发作。 NGLY1缺乏症是由NGLY1中的功能丧失突变引起的 从糖蛋白中裂解N连接的聚糖的脱糖基酶。该提议的目的是发展潜力 通过识别可能用作治疗靶标的遗传修饰剂，NGLY1缺乏症的治疗选择 并通过执行公正的小分子屏幕。 NGLY1中有大量的表型变异性 缺乏症，表明遗传背景的影响。基于表型异质性的基因 Ngly1缺乏症是未知的，但它们可能会提供有关疾病机制的见解并提供治疗性 靶向疾病改变途径的途径。 Chow Lab最近在A中进行了遗传修饰符屏幕 NGLY1缺乏症的果蝇Melanogaster模型使用遗传多样的果蝇遗传 参考面板（DGRP）。一些DGRP线在损失NGLY1时完全可行，而另一些是 100％致命。基因组广泛的关联分析确定了似乎影响致命性的61个基因。目标1 该提案将跟进这些候选遗传修饰符。对损失产生保护作用的基因 NGLY1的尤其令人感兴趣，因为它们可能是NGLY1缺乏症的潜在治疗途径。 该提案的目标2是为在Ngly1中挽救致死性的化合物进行小分子筛选 缺陷果蝇模型。屏幕将重点关注FDA批准的化合物，以简化 从我们的飞行模型到人类状况的发现的适用性。 AIM 2还解决了药物基因组学 罕见疾病的挑战。药物反应的个体差异在人口中很常见， 一些人对治疗的反应很好，一些人对药物反应不良。 DGRP 将利用用于研究遗传背景如何影响治疗功效并确定基因变异 在为NGLY1缺乏人群开发安全有效的治疗时，需要考虑这一点。 犹他大学是该项目的理想环境。赞助商Clement Chow博士已经开发了多个 果蝇疾病模型，并具有使用遗传变异来鉴定疾病修饰基因的专业知识。这 人类遗传学系促进了强大的博士后培训环境，由多个世界组成 著名的遗传学专家，其中许多人与果蝇合作。共同提案国兰德尔·彼得森（Randall Peterson）博士很高 在药物开发领域取得了成功，并具有指导成功的博士后的良好记录。这 该提案中概述的培训将使学员能够发展果蝇技能，学习新的统计 技术，在小分子药物筛查中知识渊博，产生直接适用于 人类健康，并发展成为一名独立研究科学家的技能。