# Project 3

> **NIH NIH P50** · EMORY UNIVERSITY · 2023 · $447,989

## Abstract

Project Summary
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic
cause of autism spectrum disorders (ASD). FXS is caused by the loss of functional fragile X mental retardation
protein (FMRP). Previous works have focused on the role of FMRP as a translational regulator, and many mRNA
targets of FMRP have been shown to be ASD-linked genes. Despite major progress to characterize underlying
disease mechanisms in animal models that has led to several clinical trials, including phase 3 clinical trials of
drugs modulating metabotropic glutamate and GABA receptors, improvements of behavioral and cognitive
outcomes in patients have unfortunately been largely unsuccessful. We believe that a major gap in the preclinical
phase of drug development for FXS can be addressed by the development of human FXS induced pluripotent
stem cell (iPSC) derived models, which will enable us to identify human specific therapeutic targets and evaluate
novel therapeutic approaches. Human iPSCs are pluripotent and are able to generate many different cell types.
Three-dimensional (3D) organoid culture of iPSCs has evolved from embryoid body culture, quite faithfully
following human organogenesis, and provides a new platform to investigate human brain development in a dish,
otherwise inaccessible to experimentation. We have developed FXS iPSC models, including 2D neural
progenitor cells (NPCs)/cortical neurons and 3D cortical organoids, and identified a number of FMRP target
mRNAs in the human context. Furthermore, we have observed abnormalities associated with the loss of FMRP
at molecular, cellular and electrophysiological levels in FXS iPSC models. Intriguingly, our preliminary data
suggest that PI3K inhibitors, but not mGluR5 antagonists, could rescue cellular phenotypes in human FXS iPSC
derived model systems, potentially validating the failure of positive preclinical mouse studies with negative
human trials. In this proposed study, we aim to use human specific iPSC models as translational tools to develop
novel therapeutic approaches for FXS. First, we will determine the therapeutic effects of compounds targeting
candidate pathways in FXS organoids (Aim 1). Second, we will develop CRISPR-based genomic and epigenomic
editing therapeutic approaches to reactivate FMR1 expression in FXS organoids (Aim 2). Third, we will conduct
molecular phenotype and FMR1-reactivation-based small molecule screens (Aim 3). Our proposed works will
lead to the identification of novel therapeutic targets and the development of new treatment strategies for FXS.

## Key facts

- **NIH application ID:** 10678943
- **Project number:** 5P50HD104458-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** PENG JIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $447,989
- **Award type:** 5
- **Project period:** 2020-09-25 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10678943

## Citation

> US National Institutes of Health, RePORTER application 10678943, Project 3 (5P50HD104458-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10678943. Licensed CC0.

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