# ISRIB as a promising therapeutic for Fragile X syndrome

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $65,310

## Abstract

PROJECT SUMMARY/ABSTRACT
 Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by cognitive and behavioral
difficulties including intellectual disability, anxiety, hyperactivity, and many other autistic behaviors. FXS is the
leading genetic cause of intellectual disability, affecting millions of children worldwide, however, there is currently
no cure. FXS is caused by the absence of the Fragile X Mental Retardation Protein (FMRP). This FMRP
deficiency activates the integrated stress response (ISR), promoting the internalization of AMPA receptors,
concomitant with deficits in dendritic spine maturation and turnover. These synaptic deficits likely underlie the
cognitive deficits observed in FXS. New therapeutic strategies have immense potential for the improvement of
FXS patient quality of life, however there are currently no therapies targetting the ISR. The overall objective of
this proposal is to determine the efficacy of ISR modulation by the novel drug ISRIB (ISR inhibitor) in normalizing
the synaptic and cognitive deficits observed in FXS. Our central hypothesis is that blocking the ISR with ISRIB
will stabilize spine maturation and turnover, alleviating the behavioral and cognitive deficits observed in FXS.
Utilizing an Fmr1 knockout (KO) mouse model of FXS, we will address this hypothesis in the following specific
aims: 1) Determine the effect of ISRIB treatment on synaptic phenotypes in Fmr1 KO mice and 2) Determine the
effect of ISRIB treatment on cognitive and social deficits in Fmr1 KO mice. We will address these aims using a
combination of molecular, imaging, and behavioral techniques. We will determine the effect of ISRIB treatment
on spine maturation by measuring the abundance of post-synaptic membrane-bound AMPA receptors and spine
dynamics by measuring the rate of formation and elimination. The effect of ISRIB on behavioral phenotyes will
be assayed by a battery of social and cognitive tests. The outcomes of this research will define the role of the
ISR in the etiology of FXS and has the potential to provide a foundation for the development of new strategies
for therapeutic intervention in FXS.
 I have developed a detailed, tailored development plan for my training during this award period including
technical, scientific, and professional training activities. I will build on my strong foundation in molecular biology
as well as gain technical training in array tomography, two-photon microscopy, and mouse behavioral analysis.
For scientific training, I will enroll in both formal courses as well as participate in seminars at Stanford.
Professionally, I will enhance my career development through workshops, conference participation, and grant
and manuscript writing programs. The training environment in Dr. Mourrain’s lab and at Stanford is exceptional.
In addition to my research activities, in which I will gain new technical and scientific expertise, I will participate in
a variety of development programs offered at S...

## Key facts

- **NIH application ID:** 10067005
- **Project number:** 1F32HD103451-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** ROCHELLE LYNN COULSON
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2020-07-17 → 2023-07-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067005

## Citation

> US National Institutes of Health, RePORTER application 10067005, ISRIB as a promising therapeutic for Fragile X syndrome (1F32HD103451-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10067005. Licensed CC0.

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