Repurposing FDA-Approved Drugs to Treat Major Depressive Disorder in Fragile X Syndrome
Kimberly F. Raab-Graham, PhD
Principal Investigator
Chelcie F. Heaney, PhD
Co-Principal Investigator
Wake Forest School of Medicine
Winston Salem, North Carolina
Summary
Did you know that depression is more common in those with autism and/or Fragile X?
Even more disturbing is the discovery that current treatments for depression do not work in Fragile X mice. These researchers published a study showing that standard treatments for depression need the protein FMRP to work — and people with Fragile X syndrome have little or no FMRP.
With this grant, the team will work to develop a rapid screening tool to identify FDA-approved drugs which can treat depression in people with Fragile X syndrome.
The Results
FRAXA-funded work from the Raab-Graham laboratory has advanced this project’s goal of repurposing FDA-approved drugs for major depression in Fragile X syndrome by defining synaptic and signaling mechanisms that may underlie mood dysregulation.
The team developed a rapid method to quantify synapse density, enabling efficient evaluation of candidate therapeutics (Heaney et al., 2022, Journal of Visualized Experiments). They also identified pathways linking neuronal excitability, calcium signaling, and the Fragile X protein (FMRP), including a role for DJ-1 in regulating dendritic calcium channel activity (Niere et al., 2023, PNAS) and evidence that DJ-1–mediated repression of FMRP may disrupt protein networks relevant to neuropsychiatric symptoms (Uneri et al., 2024, Journal of Alzheimer’s Disease).
In addition, a review of excitatory GABA signaling highlights mechanisms that may contribute to altered mood and circuit function in Fragile X (McArdle et al., 2024, Frontiers in Psychiatry). Together, these results provide mechanistic targets and screening tools that support drug repurposing strategies for depression in Fragile X.
The Science
By Kimberly F. Raab-Graham, PhD
People with Autism Spectrum Disorder (ASD) have an increased risk of developing Major Depressive Disorder (MDD) by the time they are 30 years old compared to people without ASD. Fragile X syndrome (FXS) is the single leading genetic cause of ASD, and caretakers report mood and depression as priorities for treatment development. FXS results from the functional loss of the gene FMR1; this loss prevents expression of the Fragile X Mental Intellectual Disability Protein (FMRP). Importantly, people with MDD and those with ASD have less FMRP expression.
Our recent experiments show that current treatments for MDD are ineffective in a standard preclinical mouse model for FXS, which indicates that these treatments need the protein FMRP to work. This proposal builds upon our published work that identifies how antidepressants induce FMRP-dependent changes that increase the number of connections and strengthen communication between brain cells. Using a computational approach that predicts how to increase these connections in the absence of FMRP, we will identify FDA-approved drugs to test as potential antidepressants in a preclinical model of FXS.
These studies aim to develop a rapid screening process for therapeutics with the potential for repurposing. This rapid screening process will decrease the amount of time it takes for a drug to go from bench-to-bedside. The proposed studies develop a highly innovative and novel approach to address the need for effective treatments of MDD in people with FXS.
Grant Post Revisions
- 2024/12 - Results Added.
- 2022/04 - Grant Renewed.
- 2021/06 - Original grant post published.