# Identifying Genetic Modifiers and Potential Therapeutics for NGLY1 Deficiency

> **NIH NIH F32** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $26,422

## Abstract

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...

## Key facts

- **NIH application ID:** 10407482
- **Project number:** 5F32GM139349-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kevin A. Hope
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $26,422
- **Award type:** 5
- **Project period:** 2021-06-01 → 2022-09-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407482

## Citation

> US National Institutes of Health, RePORTER application 10407482, Identifying Genetic Modifiers and Potential Therapeutics for NGLY1 Deficiency (5F32GM139349-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407482. Licensed CC0.

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