# The FMR1 CGG repeat as functional element and therapeutic target in Fragile X associated disorders

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2024 · $500,047

## Abstract

The FMR1 repeat as functional element and therapeutic target in Fragile X disorders.
Short Tandem repeat (STR) expansions cause ~50 inherited neurological diseases. However,
disease associated loci represent only a small fraction of the ~3 million STRs present in the
human genome. Despite their importance in human disease, the broader question of what
intrinsic roles these repetitive elements play in normal neurobiology is largely unexplored. We
recently discovered a conserved and native function for CGG repeats in the 5’ UTR of FMR1.
This repeat expands in Fragile X Syndrome (FXS, a common cause of autism and intellectual
disability) and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS, an age related
neurodegenerative disorder). At normal and expanded sizes, FMR1 CGG repeats trigger
translation of multiple cryptic proteins in the absence of an AUG start codon (CGG RAN
translation). We recently described how CGG repeats and RAN translation act as an upstream
open reading frame (uORF) to impede translation of the fragile X protein, FMRP. Using a
combination of reporter assays as well as RAN translation blocking antisense oligonucleotides
(RAN ASOs) in human neurons, we found that both the CGG repeats and RAN translation
inhibit FMRP synthesis basally. This inhibition is alleviated by metabotropic glutamate receptor
(mGluR) activation, which underlies a form of synaptic plasticity important for learning and
memory and implicated in Fragile X-associated disorders. Based on these findings, our central
hypothesis is that RAN translation and tandem microsatellite repeats have native functions in
the regulation of the genes in which they reside, and that aberrancies in these native functions
contribute to human disease. Our goals in this project are 3 fold: 1) Determine the mechanisms
by which CGG repeats and RAN translation regulate FMRP synthesis, 2) investigate what
consequences result from disrupting this regulatory loop in both mouse models and human
neurons, and 3) evaluate whether ASOs can be used to simultaneously suppress RAN
translation and activate FMRP synthesis in FXS and FXTAS human neurons as a step towards
novel therapeutic development.

## Key facts

- **NIH application ID:** 10907683
- **Project number:** 5P50HD104463-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Peter K Todd
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $500,047
- **Award type:** 5
- **Project period:** 2020-09-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907683

## Citation

> US National Institutes of Health, RePORTER application 10907683, The FMR1 CGG repeat as functional element and therapeutic target in Fragile X associated disorders (5P50HD104463-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907683. Licensed CC0.

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