Our research strategy is intentionally focused on one overarching goal: accelerating the development of treatments for CTNNB1 Syndrome. Guided by our Scientific Advisory Board, we prioritize research that can directly advance our understanding of how reduced CTNNB1 function causes disease and, most importantly, identify ways to restore, replace, or compensate for that lost function.
Within this framework, we have built a connected and growing research ecosystem designed to move from understanding CTNNB1 biology to developing and testing potential treatments. This includes identifying and validating therapeutic targets, discovering and repurposing drugs that may modify the underlying biology, and developing preclinical models that can help us understand disease mechanisms and reliably evaluate potential therapies.
Michele H. Jacob, PhD
Associate Professor, Developmental, Molecular and Chemical Biology, Tufts University
GSK3i Small Molecule
October 2019 - Present
$544,000
Dr. Jacob was the first recipient of CCC funding and her important work continues to be funded by our organization. Her research uses a haploinsufficient mouse model of CTNNB1 syndrome which carries a whole-body deletion of one CTNNB1 allele. These mice were shown to have behavioral phenotypes analogous to symptoms seen in CTNNB1 syndrome: were genotyped and studied through in particular, behavioral assays showed that the mice displayed deficits in learning, locomotion, and motor skills. Her lab further showed that the mice have reduced β-catenin levels, a loss of β-catenin association with its “collaborator” protein, N-Cadherin, and that there was less gene expression in genes that β-catenin is responsible for upregulating. Her lab’s work also gave insight into how neuron firing is altered in CTNNB1 haploinsufficient mice.
Importantly, Michele’s team showed that giving the CTNNB1 mice a small molecule drug was able to rescue the CTNNB1 mice’s behavioral and cellular phenotypes. This small molecule drug is a GSK3 inhibitor: GSK3 is a protein which normally causes β-catenin to get destroyed by the proteasome, the “recycling center” of the cell. The small molecule drug works by stopping GSK3 from being able to mark β-catenin for destruction, thereby raising the overall levels of β-catenin in the cell.
Her team is now collaborating with the Broad Institute and The National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH), to optimize the small molecule into a lead candidate for clinical trials.
Wendy K. Chung, MD, PhD
Chief, Department of Pediatrics, Boston Children’s Hospital
Mary Ellen Avery Professor of Pediatrics, Harvard Medical School
CTNNB1 Natural History Study
June 2023 - Present
$185,000
This project involves annual in-person assessments by a team of clinical experts paired with online caregiver-reported surveys via Simons Searchlight to track the progression and variability of the condition over time. Through these efforts, we are validating clinical endpoints and biomarkers that will be essential for future clinical trials, while also generating the data needed to design therapeutic interventions and support regulatory submissions.
Dr. Chung’s team published an analysis of the first cohort, and they continue to analyze the data year-over-year for longitudinal insights.
Natural history studies are especially critical in rare diseases like CTNNB1 syndrome, where little is known about how the condition changes over time. This study will shed light on unanswered questions, such as genotype-phenotype correlations and how CTNNB1 symptoms change as a person ages. By collecting consistent, long-term data, researchers can better understand the range of symptoms, identify meaningful measures of improvement, and establish the baseline information that regulators require before approving clinical trials. This work ensures that when potential therapies are ready to be tested, the community is fully prepared to move them forward.
Clement Chow, PhD
Associate Professor in the Department of Human Genetics, University of Utah School of Medicine
Drosophila Drug Screen
November 2024 - July 2025
$76,849
As we work towards precision therapeutics for CTNNB1 patients, it is also important to landscape medications that are already FDA-approved. CCC funded Dr. Chow’s team to conduct a high-throughput screen of over 1,600 FDA-approved compounds in a drosophila (fruit fly) model of CTNNB1 Syndrome.
Dr. Chow’s team was able to identify twenty-eight drugs that improved the phenotype seen in the fly model. Some of the key drug classes present on the hit list include: serotonin, histaminergic, antimalarial, and sodium channels.
Clinical and pharmaceutical will review the results and advise which compounds to investigate further, and by which methods.
Mohammad Moshahid Khan, PhD
Associate professor, Department of Neurology, College of Medicine at the University of Tennessee Health Science Center
Gut Microbiome in CTNNB1 Syndrome
November 2024 - Present
CCC provided biosamples for this project
Dr. Mohammad Moshahid Khan’s research explores whether the gut microbiome—the community of microorganisms living in the digestive tract—may contribute to CTNNB1 syndrome. Because CTNNB1 helps maintain the intestinal barrier as well as supporting brain development, his team is investigating how changes in its function might affect communication between the gut and brain. Preliminary analyses of stool samples from individuals with CTNNB1 syndrome found differences in the diversity and composition of gut bacteria compared with controls, including reduced levels of Akkermansia, a bacterium associated with gut barrier health.
The team also identified predicted differences in microbial pathways involved in energy production, vitamin metabolism, and other biological processes. These findings raise questions about whether altered gut bacteria and the substances they produce could influence symptoms of CTNNB1 syndrome. Ongoing and future studies will examine these substances and test biological mechanisms to determine whether the microbial changes contribute to disease or are associated with it. The long-term goal is to identify safe, effective microbiome-based treatment strategies; the findings presented are an early step and do not yet establish a treatment benefit.
Jeff Coller, PhD
Professor of Molecular Biology and Genetics, Johns Hopkins School of Medicine
mRNA Booster Therapeutic
January 2025 - Present
$63,000
Dr. Jeff Coller and his team developed an innovative therapeutic approach known as mRNA boosters to correct haploinsufficiency disorders, including CTNNB1 syndrome. These synthetic oligonucleotides mimic the natural poly(A) tail of messenger RNAs, stabilizing transcripts to extend their lifespan so they can continue to give rise to protein.
Initial studies in neuronal cell models confirmed that the boosters could bind poly(A)-binding proteins and enhance protein production. To improve durability and efficacy, chemically modified versions were designed with protective linkages and optimized poly(A) tail lengths. These next-generation boosters demonstrated increased stability, persisting for over a week in human neuronal cells, and produced significantly higher expression of target proteins.
Application to human iPSC-derived neurons engineered to have CTNNB1 loss-of-function showed that booster treatment elevated β-catenin protein levels by approximately 1.5–2-fold. Importantly, the restored protein was functional, activating canonical signaling pathways disrupted in CTNNB1 syndrome. Comparable results were obtained in SYNGAP1 models, underscoring the broad therapeutic potential of this platform for haploinsufficiency disorders.
This work establishes mRNA boosters as a versatile and mutation-independent therapeutic strategy. By selectively enhancing expression from the intact allele, boosters provide a means of correcting protein deficits across the full spectrum of CTNNB1 mutations. Ongoing studies aim to comprehensively assess capability for translation to human patients, including preclinical testing in animal models.
CTNNB1 Biorepository
June 2023 - Present
$27,000 + maintenance & distribution costs
CTNNB1 Connect and Cure collaborates with COMBINEDBrain, a nonprofit research consortium, to host a CTNNB1 biorepository. A biorepository is a secure, organized collection of patient-derived biological samples that are made available to investigators to research CTNNB1 syndrome. Our CTNNB1 biorepository stores samples from patients with CTNNB1 mutations as well as from unaffected family members who serve as controls. These samples include: blood, plasma, peripheral blood mononuclear cells (PBMCs), urine, stool, cerebrospinal fluid (CSF), and nasal swabs (nasal endothelial cells). Our repository is essential for advancing CTNNB1 research because it allows scientists to understand disease mechanisms by examining how specific mutations affect cells and molecular pathways. Control samples help isolate changes specific to CTNNB1 syndrome versus normal variation. Our CTNNB1 biorepository serves as a foundational resource for understanding the syndrome and designing effective treatments. To date, samples in the biorepository have been used for important proteomics and gut microbiome studies.
Sophie Marek, MS, CGC
Rutgers University
CTNNB1 Disease Concept Model
Genetic counselor Sophie Marek’s research explores how CTNNB1 syndrome affects everyday life for individuals and their families. As part of her graduate thesis at Rutgers University, she reviewed more than 50 scientific articles and conducted 15 interviews involving 16 parents and caregivers to develop a disease concept model—a framework describing symptoms and their impact on daily life.
The interviews reinforced recognized challenges with communication, movement, and behavior while highlighting experiences that were not fully captured in the literature reviewed, including difficulty falling and staying asleep, frustration, and the use of nonspeaking communication. Caregivers also described their children’s strong desire to communicate, underscoring the importance of understanding abilities and needs beyond clinical descriptions.
The study also documented the broader effects of CTNNB1 syndrome, including support needed for daily activities and school, frequent therapy and medical appointments, and the emotional, social, and financial demands on caregivers. Families emphasized the value of supportive communities, including connections through CTNNB1 Connect & Cure, which helped with recruitment and interview preparation. By bringing caregiver experiences into the research record, this work provides a fuller picture of CTNNB1 syndrome and can help inform family resources, clinical conversations, and future research priorities that reflect what matters most to families.