# Mitochondrial dysfunction in Fragile X: Mechanisms and treatments

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $508,402

## Abstract

Abstract: Fragile X Syndrome (FXS), the most common cause of intellectual disability and autism, is caused by
the loss of FMR1 gene function. Drosophila and mouse models of FXS have been developed that are based on
loss of function mutations of their respective homologues of FMR1, dfmr1 and Fmr1. These models display
several phenotypes that bear similarity to Fragile X patient symptoms. In previous studies, we and others have
identified reduced cAMP levels and increased insulin/PI3K signaling as defects in the Fragile X animal model
brains. Our work on a Drosophila FXS model demonstrated that restoration of the cAMP deficit, by treatment
with PDE4 inhibitors, restores behavior and memory. We have also shown that genetic and pharmacological
manipulations that restore normal insulin signaling levels rescue behavioral and memory deficits. Our findings
for both pathway defects have been reproduced in the mouse FXS model. Further, we discovered that metformin
treatment of the FXS Drosophila model also restores memory and behavior, a finding that too has been replicated
in the mouse FXS model. In sum our studies have determined that three seemingly distinct approaches, e.g.
increasing cAMP levels, decreasing insulin signaling and metformin treatment can restore behavioral and
cognitive phenotypes displayed by the FXS animal models. Importantly two of these findings are being pursued
clinically and have given rise to promising results. A novel PDE4 inhibitor, BPN14770, has been tested in a
phase II clinical trial with Fragile X adults. The results of this study have shown that treatment with this compound
can significantly improve cognitive and life skills in Fragile X adult aged 18 to 45. Also, several case studies of
Fragile X patients treated with metformin have reported improvements in cognitive and social domains. These
findings have led to the initiation of clinical trials with metformin. Given the clinical relevance of our findings, an
important question that we will address in this study is how these three seemingly different approaches act to
restore behavior and cognition in a FXS animal model. Our preliminary studies indicate that they converge on
improving mitochondrial function. In recent studies we have identified robust mitochondrial deficits displayed by
the Drosophila FXS model and FXS patient derived cells. We have also determined that the mitochondrial master
regulator PGC-1a is significantly decreased in the Drosophila model and in FXS patient derived cells. Importantly
we have determined that the mitochondrial defects and PGC-1a are improved by metformin treatment and the
genetic reduction of insulin signaling. We have also demonstrated that independently increasing PGC-1a
expression improves mitochondrial function and a behavioral phenotype. In our proposed studies we will perform
experiments to verify that the restoration of the signaling pathway defects, as well as metformin treatment
increase both PGC-1a expression and mitochond...

## Key facts

- **NIH application ID:** 10843325
- **Project number:** 5R01NS129903-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** THOMAS A JONGENS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,402
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843325

## Citation

> US National Institutes of Health, RePORTER application 10843325, Mitochondrial dysfunction in Fragile X: Mechanisms and treatments (5R01NS129903-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10843325. Licensed CC0.

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