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 knowledgeabl...