# CGG repeat associated translation in Fragile X gene function and disease

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,922

## Abstract

Project Summary
Intermediate expansion of a CGG repeat in the 5’ UTR of the FMR1 gene (between 55-200 repeats) underlies
an age-related neurodegenerative disorder, Fragile X Syndrome and Fragile X-Associated Tremor/Ataxia
Syndrome (FXTAS). While full mutations (>200 repeat expansions) resulting in FXS typically lead to
methylation and silencing of FMR1 expression, FXTAS patients express normal or elevated amounts of FMR1
mRNA but have reduced FMRP. Large transcribed CGG repeats are potentially toxic as RNA or by triggering
Repeat associated non-AUG initiated (RAN) translation, allowing for production of toxic homopolymeric
peptides that contribute to neurodegeneration. Therefore, effective therapies for FXTAS need to
simultaneously block CGG RAN and enhance production of FMRP. Previous data provides evidence that RAN
translation inhibits translation of downstream FMRP, but may also play a critical role in regulating mGluR-LTD,
a form of synaptic plasticity. This finding was shown at normal repeat sizes in addition to the expanded
condition. In this proposal, I will investigate the native role of RAN translation in regulating FMRP synthesis
both basally and upon stimulation of the metabotropic glutamate receptor at the endogenous FMR1 locus in
patient stem cell-derived neurons. This work will determine the potential of blocking RAN translation as a
method to simultaneously reduce toxic RAN products and enhance FMRP. Additionally, I will directly test this
therapeutic mechanism utilizing an antisense oligonucleotide that selectively targets RAN initiation sites (RAN
ASOs) on the FMR1 transcript. In reporter systems and human cell lines, these ASOs suppress RAN
translation at both normal and expanded repeat sizes. RAN ASOs also enhanced endogenous FMRP, reduced
toxic RAN protein, FMRpolyG, and enhanced neuronal survival in neurons derived from a patient with an
unmethylated full mutation (UFM), in which FMR1 is efficiently transcribed, but poorly translated. In this project,
I will treat FXTAS patient stem cell-derived neurons with RAN ASOs and evaluate ASO-mediated amelioration
of disease-specific deficits in neuronal survival, calcium signaling, and neurite outgrowth. Together, these
experiments would demonstrate a native function for CGG RAN in regulating FMRP synthesis and
demonstrate that targeting RAN translation has the potential to correct multiple disease relevant features in
Fragile X-associated disorders.
Furthermore, the training described in this proposal will prepare me for a future in translational research and
modeling of neurological disease. The activities under this award will train me to thrive in a future research
career and prepare me to train the next generation of scientists.

## Key facts

- **NIH application ID:** 9989286
- **Project number:** 1F31NS113513-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Shannon Wright
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,922
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989286

## Citation

> US National Institutes of Health, RePORTER application 9989286, CGG repeat associated translation in Fragile X gene function and disease (1F31NS113513-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9989286. Licensed CC0.

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