A Brighter Future for Neurodevelopmental Disorders
At the FOXG1 Research Center, our primary goal is to advance research for FOXG1 syndrome, striving to find cures for children affected by this rare genetic disorder.
Beyond FOXG1 syndrome, our work also extends to targeting autism and other neurodevelopmental disorders, contributing to broader scientific understanding and potential treatments.
Our work is driven by a commitment to discover new insights and develop therapies that can improve the lives of those affected. We're dedicated to turning scientific breakthroughs into real-world hope and brighter futures.
“We hope to find a way to alleviate symptoms in people with FOXG1 syndrome or other disorders in which FOXG1 plays important roles, such as autism spectrum disorder and schizophrenia.”
Dr. Soo-Kyung Lee, Director of FOXG1 Research Center
Our Research Focus
Understanding FOXG1 & Beyond
Studying FOXG1 syndrome isn’t just about understanding a single rare condition—it's about unlocking key insights into the broader landscape of neurodevelopmental disorders.
The FOXG1 gene plays a crucial role in brain development, and mutations in this gene result in a spectrum of symptoms that vary in severity from patient to patient. This variation—ranging from mild to severe—makes it particularly challenging to develop treatments that work for all affected children.
Common symptoms of FOXG1 syndrome include cognitive and physical disabilities, epilepsy, and features seen in autism spectrum disorder, such as repetitive movements, impaired social interaction skills, and severe intellectual disability. By exploring these complexities, our research aims to uncover solutions that address the diverse needs of each patient while contributing to our understanding of related conditions like autism.
This broader understanding helps us develop targeted therapies that could benefit not only those with FOXG1 syndrome but also individuals affected by various neurodevelopmental disorders.
Our Research Models & Approaches
Mouse and iPSC Models
At the FOXG1 Research Center, we’ve developed advanced models to study FOXG1 mutations, including both mouse and induced pluripotent stem cell (iPSC) lines.
These models are instrumental in replicating the broad spectrum of FOXG1 phenotypes seen in humans, providing critical insights into how FOXG1 functions beyond birth and fueling our hope for potential therapies.
Mouse
One of the most groundbreaking achievements in our research has been the successful application of viral gene therapy in mice with FOXG1 syndrome. These mice, which exhibit symptoms similar to those seen in humans—such as challenges in learning, memory, social interaction, and movement—have shown remarkable improvement following postnatal gene therapy. By introducing FOXG1 protein into mice shortly after birth, we’ve observed a significant rescue of normal functions, with the treated mice behaving like healthy ones.
These results we found are encouraging, suggesting that early intervention could mitigate even structural deficiencies caused by FOXG1 mutations. Our research currently involves over 15 different strains of FOXG1-related mouse lines, which we’ve developed in our lab or received from external sources. These strains are being used for a variety of studies, including behavioral tests and brain analysis at different developmental stages—embryo, neonatal, young mice and adult mice. This range of models allows us to investigate the neurodevelopmental functions and impacts of FOXG1 mutations across different ages and severity levels.
Our goal is to develop effective and safe therapeutic strategies that could improve the quality of life for patients with FOXG1 syndrome and related conditions. While we know we cannot reverse the damage already done in individuals with this condition, our research offers hope for modifying the disease's effects and enhancing the lives of those affected.
In addition, various mouse behavior experiments are being conducted by a team of mouse behavior experts at FRC to test symptoms of FOXG1 syndrome patients, such as defects in motor functions, reduced social ability, sensory overload, seizure activity and poor intellectual ability.
hiPSC Models
The FOXG1 Research Center has successfully differentiated human induced pluripotent stem cells (iPSCs) into cortical neurons in vitro through preliminary research. Based on this, we are currently differentiating iPSCs derived from W308X patients into neurons and analyzing their characteristics in various methods (such as analyzing neural differentiation efficiency, Sholl analysis for dendrite formation, sub-localization of FOXG1 protein, mitochondrial characteristics, etc.). In particular, through collaboration with the mouse model team within the Center, we were able to obtain promising results both in vivo and in vitro by comparing and analyzing the findings through molecular biology. All of these were very interesting and significant, and we plan to publish the related data in a future journal.
Currently, the FOXG1 Research Center has various FOXG1 mutant patient-derived hiPSCs (Q86Pfs, G224S, G169G, etc.). Our goal is to utilize these cells to understand the characteristics of neurons from FOXG1 mutant patients in vitro and to develop a basis for personalized treatment for individual patients or specific mutations by conducting drug screening using these neurons.
Although we understand that these efforts cannot reverse the damage that has already occurred, the FOXG1 Research Center aims to develop effective and safe treatment strategies to alleviate the symptoms of FOXG1 syndrome and related disorders. By doing so, we hope to improve the quality of life not only for the patients but also for everyone involved.
Therapeutic Development
Our research has uncovered how FOXG1 functions not only during early brain development but also after birth.
This has provided us with critical insights into its role in neurodevelopmental disorders. This foundational work has been essential in guiding our efforts to develop targeted therapies.
Building on this knowledge, we are now focused on translating our discoveries into practical treatments that can move into clinical trials. Our ongoing research includes testing innovative therapeutic strategies, such as viral gene therapy, which has already shown promising results in preclinical studies using mouse models. These efforts are aimed at developing therapies that are not only effective but also safe for children with FOXG1 syndrome.
Our ultimate goal is to create treatments that can be administered early in life, offering the best chance of mitigating the symptoms and improving the quality of life for those affected. We are committed to ensuring that these therapies are thoroughly tested and refined, so they can provide real hope for families dealing with FOXG1 syndrome and other neurodevelopmental disorders.
Since we have seen such promising preclinical results from our viral gene therapy, we are now proceeding with the next steps towards human clinical trials, which include several forms of extensive safety and efficacy testing.
Through the work both in our facilities and in collaboration with an experienced drug development team at Charles River Laboratories (CRL), we are treating our animal models with varying amounts, or dose levels, of our gene therapy vector.
Through these studies, we will be able to ensure that this treatment is specifically targeting the areas of the body where it is needed the most, and not causing any harmful, unintended effects elsewhere.
Additionally, we will get a clear idea of the dose range that we can give to human patients that have the best chance of significantly improving their symptoms without causing harmful side effects. We expect to complete this cycle of testing in early-mid 2025, which will allow us to then begin preparing a proposal to submit to the FDA, who will determine whether or not we can be approved to begin preparing for human clinical trials.
Clinical Trials
Our Current Research Focus:
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Although the brain comprises only 2% of our body mass, it represents the single largest source of energy consumption in the human body. The primary energy-producing centers of our cells are known as mitochondria. There is a strong link between mitochondrial dysfunction and neurodevelopmental disorders, as damage to these energy centers is known to contribute to clinical symptoms like cognitive impairment and epilepsy. As these symptoms are also observed in FOXG1 Syndrome patients, our team is currently investigating how mitochondrial dysfunction may play a role in FOXG1 Syndrome disease pathology. Determining this link will allow us to explore even more new avenues for treatment generation.
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The brain functions in a coordinated manner through rapid signals transferred between various sub-regions, resulting in functional outputs. A critical region in this process is the striatum, which receives inputs from areas such as the cortex and thalamus. The striatum integrates these signals and sends outputs that regulate movement, decision-making, motivation, and reward-based behaviors via dopamine signaling. Dysfunction of the striatum is associated with impaired motor control, cognition, repetitive behaviors, and social interaction difficulties. These symptoms are also seen in FOXG1 syndrome patients, highlighting the importance of understanding the striatum’s role in the syndrome's pathology. Our team is currently investigating the role of the striatum in FOXG1 syndrome with the goal of identifying potential treatments that can alleviate the cognitive, motor, and social challenges faced by patients.
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MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the production of proteins by controlling gene expression. They typically bind to specific sequences in the 3′ untranslated regions (3′ UTR) of target mRNAs to fine-tune protein expression. FOXG1 3’UTR has been reported to host many miRNA target sequences. FOXG1 haploinsufficiency or the presence of a single functional FOXG1 gene in FOXG1 syndrome patients leads to decreased FOXG1 protein which results in neurodevelopmental defects. Understanding the FOXG1 regulation at the post-transcriptional level via miRNA can help us to improve the stability and increase the expression of FOXG1 protein. It will also help us to explore miRNA as a therapeutic approach to help FOXG1 syndrome patients.
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Gene therapy is the treatment of a disease through transferring genetic material into patients. In the recent several years, gene therapy has experienced rapid progress and achieved huge success. For the gene therapy, recombinant adeno-associated virus (AAV) vectors have been developed to successfully transduce various cell types and cross the blood-brain barrier (BBB).
Despite the recent advances in AAV9-directed gene therapy for central nervous system diseases, the efficacy of this technology in correcting prenatal brain malformations associated with neurodevelopmental disorders remains unclear.
Therefore, our team produced the AAV-Foxg1 virus and injected it into the FOXG1 mutant mouse brain by intra-cisterna magna (ICM) and intracerebroventricular (ICV) injection techniques. This therapy showed the rescuing effect of brain structure and cell population. AAV therapy is now an ongoing project and our team expects that AAV9-directed gene therapy can be explored to treat neurodevelopmental disorders with brain structural abnormality.
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In epilepsy, seizures can evoke cardiac rhythm disturbances such as heart rate changes, conduction blocks and arrhythmias, which can potentially increase risk of sudden unexpected death in epilepsy. Electroencephalography (EEG) is a widely used clinical diagnostic tool to monitor seizures in patients. Symptoms of FOXG1 syndrome usually begin in infancy, often in the second month of life. Irritability occurs first, with repeated seizures (epilepsy) occurring later. Nowadays, our labs (of Jae and Soo) in FRC are setting up the EEG recording system for FOXG1 mutant mouse models. This system will help us to find out the seizure patterns and give us the guideline for treating FOXG1 syndrome patients with seizure symptoms.
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The transcription factor Forkhead box G1 (FOXG1) is expressed in the developing nervous system and plays a critical role in forebrain development. Single allelic mutations in the gene encoding FOXG1 lead to FOXG1 syndrome, which manifests a wide range of symptoms depending on locations and types of Foxg1 mutations.
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This project is dedicated to unraveling the complexities of FOXG1 syndrome, with a particular focus on the diverse functions of FOXG1 and their implications for potential therapeutic interventions. We employed Cut&Run technology to analyze genome-wide binding profiles of FOXG1 in the cortex, hippocampus and striatum of patient-specific FOXG1 mutant mouse models. Our aim is to dissect FOXG1’s genetic regulatory networks and to identify potential targets across different neurological disorder contexts.
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To elucidate how patient-specific FOXG1 mutations translate into diverse phenotypic symptoms, we conducted a combined analysis of single-cell transcriptomics and chromatin accessibility on different FOXG1 mutant mouse models. This multi-omics approach establishes a direct connection between chromatin states and their underlying gene regulatory networks in an unbiased manner.
By integrating single-cell transcriptomics and chromatin accessibility landscapes, we aim to infer cell type-specific gene regulatory networks, and to identify cis- and trans-regulatory elements that are differentially activated in specific cell types during the pathological progression of diverse FOXG1 mutations-induced symptoms.
Our multi-omics study will serve as a reference to determine how the chromatin accessibility landscape changes in FOXG1 syndrome. Additionally, it will provide unprecedented insight into the mechanisms by which FOXG1 coordinates with cell type-specific key partners to regulate cell identity and fate transitions in distinct neurological disorder conditions. This comprehensive understanding will help us identify novel potential therapeutic targets for FOXG1 syndrome and related conditions.
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Approximately 14% of the 122 participants enrolled in the FOXG1 registry have mutations resulting in premature termination codons, which disrupt messenger RNA (mRNA) and lead to early termination of protein synthesis. To address this issue, tRNA therapeutics present a promising solution by enabling the bypass of these mRNA stoppages without altering the underlying genetic code.
In this research, we introduced a single suppressor tRNA (sup-tRNA) into cells expressing truncated FOXG1, successfully demonstrated its ability to read through premature stop codons and restore full-length protein production. We are now administering AAV-sup-tRNA to mouse models with FOXG1 truncating mutations, evaluating therapeutic efficacy across various brain tissues following a single treatment.
The success of this approach will not only deepen our understanding of FOXG1 syndrome but also contribute to the development of novel treatment strategies for this neurological disease. This innovative research represents a significant step forward in addressing the underlying molecular mechanisms of FOXG1 syndrome. It offers hope for future targeted therapies, paving the way for similar therapeutic approaches in other genetic disorders characterized by premature termination codons.
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Our preliminary genomic and single cell multi-omics studies have suggested that FOXG1 syndrome shares molecular pathways with other neurological disorder conditions, including autism spectrum disorder (ASD) and Huntingdon’s disease. By exploring these shared pathways, we may uncover common therapeutic strategies that could be effective across multiple conditions, leading to more efficient drug discovery and development processes. This approach not only advances our understanding of FOXG1 syndrome but also contributes to the broader field of neurological research, potentially benefiting patients with a range of related disorders.
In summary, we believe there is a unique opportunity to make a significant impact on the lives of individuals affected by FOXG1 syndrome and other neurological diseases.
Collaboration & Innovation
Partnering for Progress
Our work at the FOXG1 Research Center is strengthened by our close collaboration with the FOXG1 Research Foundation (FRF) and scientists working on different aspects on the project funded by grants received from FRF. This partnership is vital in accelerating our research efforts and moving potential therapies from the lab to clinical trials.
By working together, we combine resources, expertise, and shared commitment to bringing life-changing treatments closer to reality for those affected by FOXG1 syndrome and related neurodevelopmental disorders.
Make an Impact Today
Support our mission by contributing a donation to FOXG1 Research Center. We work closely with FOXG1 Research Foundation. All donations can be made directly to FRF to support our efforts.
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