Professor Michele Jacob to Advance the First-Ever Therapeutic for CTNNB1 Syndrome

June 30, 2025

Professor Michele Jacob, a distinguished neuroscientist at Tufts University School of Medicine and one of ten 2024 Oxford-Harrington Rare Disease Scholar Award recipients, is leading pioneering research to address a critical unmet need in rare disease: the development of the first targeted treatment for CTNNB1 syndrome.  

Supported by the Oxford-Harrington Rare Disease Centre (OHC), her work could significantly improve the lives of individuals with this complex neurodevelopmental condition.

A Diagnosis Without a Cure

CTNNB1 syndrome is a rare genetic disorder caused by mutations in the CTNNB1 gene, which encodes the essential protein beta-catenin. Diagnosed only through genetic testing and first identified in 2012, the condition leads to reduced levels and impaired function of the beta-catenin protein, disrupting key processes in brain development and function.  

Children with CTNNB1 syndrome typically exhibit developmental delays within the first months of life, and often face significant lifelong challenges with learning, speech, mobility, and independence. Currently, there are no treatment options beyond supportive care. 

Professor Jacob says: "My awarded project focuses on developing an efficacious, safe small molecule therapeutic treatment for CTNNB1 syndrome, a rare neurodevelopmental disorder with no current treatment options. This syndrome is characterised by cognitive and motor disabilities and is caused by de novo heterozygous loss-of-function pathogenic variants that span the CTNNB1 gene." 

Professor Jacob and her team have been studying the CTNNB1 gene and its role in brain function for years. Her lab has demonstrated the consequences of pathogenic CTNNB1 gene mutations and reduced beta-catenin protein levels in the brain, linking them to intellectual disability and autism spectrum disorders. 

Advancing Preclinical Insights into Treatments  

With OHC’s support and a team of expert therapeutic development advisors, Professor Jacob is now advancing her foundational research further.  

Professor Jacob said: "Our preclinical mouse and CTNNB1 patient cell studies are identifying a small molecule treatment that corrects the core molecular pathology and phenotypes, suggesting a promising therapeutic with potential to enhance the independent functioning of individuals with this syndrome." 

Her lab has identified a promising therapeutic approach using a highly selective inhibitor of glycogen synthase kinase 3 (GSK3), a natural suppressor of beta-catenin. In preclinical studies, this small molecule restored beta-catenin levels and significantly improved outcomes, even when treatment began in late adolescent mice already displaying symptoms. 

The project is now focused on identifying the safest and most effective version of this GSK3 inhibitor, in collaboration with medicinal chemists. The Jacob lab is testing optimised prodrugs for potency, brain exposure, and selectivity with the goal of identifying the most efficacious and safe lead drug candidate that significantly normalises beta-catenin levels in patient-derived cell models. Her team is building a compelling preclinical data package to attract industry collaboration and progress towards clinical trials. 

Driven by Patient Collaboration 

Professor Jacob’s research into CTNNB1 syndrome took a turn in 2019 when she was contacted by a mother seeking help for her child. The encounter connected her with CTNNB1 Connect and Cure, a newly founded patient advocacy group, with whom she has remained in close collaboration ever since.  

Insights from the CTNNB1 Connect and Cure community continue to shape the direction of her work and underscore the urgency of developing an effective therapy. Professor Jacob says that "Developing a treatment that improves the core molecular pathology and increases learning and motor function would be transformative for CTNNB1 syndrome patients and their families." 

Looking Ahead 

Beyond CTNNB1 syndrome, Professor Jacob's research may have broader implications. Other intellectual disability and autism-linked disorders also involve beta-catenin dysfunction, which means that the therapeutic strategies developed by the Jacob lab could ultimately benefit a wider range of neurodevelopmental conditions.