Unlocking the Molecular Origins of CTNNB1 Syndrome: A Collaborative Research Effort
On Rare Disease Day, researchers at the Biofisika Institute (CSIC, EHU) are making strides in understanding the molecular basis of CTNNB1 neurodevelopmental syndrome, a rare genetic disorder affecting brain development. Despite fewer than 50 diagnosed cases in Spain, rare diseases collectively impact nearly three million individuals worldwide, highlighting the critical need for dedicated research.
Understanding CTNNB1 Syndrome and the Role of Beta-Catenin
CTNNB1 syndrome is linked to alterations in the beta-catenin protein, a crucial component in both embryonic development and ongoing brain function. Beta-catenin plays a vital role in cell adhesion, providing tissues with structural integrity and mechanical strength. These processes are fundamental for brain formation and the creation of synapses – the connections that underpin learning and memory. Mutations in the CTNNB1 gene often result in incomplete or improperly folded beta-catenin proteins, hindering their ability to function correctly and disrupting critical brain development processes.
A Multi-Institutional Collaborative Approach
The research project, led by Sonia Bañuelos, a researcher at the Biofisika Institute and a lecturer in the Department of Biochemistry and Molecular Biology at the University of the Basque Country (EHU), is a collaborative effort involving several Basque institutions. The team includes neuropsychologists from the University of Deusto, molecular genetists from the Biobizkaia Institute at Cruces University Hospital, and researchers utilizing the brain organoid platform at the Achucarro Neuroscience Center. The Spanish Association of CTNNB1 Patients is also actively involved in the initiative, providing valuable insights and support.
Leveraging Biophysics, AI, and Brain Organoids
The team at the Biofisika Institute is employing advanced tools based on the three-dimensional structure of proteins to predict how mutations affect the interaction between beta-catenin and cadherin, key components of cell adhesion complexes. These predictions are then validated through biophysical techniques in the laboratory. Mutated versions of the protein, corresponding to real cases identified in a Spanish cohort, are produced in bacteria for analysis. Brain organoids are utilized to more accurately model the impact of these alterations on nervous tissue development.
Towards Future Therapies
While currently focused on basic research, the findings from this study hold promise for the future development of rationally designed therapies. “Our goal is to understand how these mutations prevent the brain from forming correctly. Understanding the mechanisms at the molecular level is essential so that specific therapies can be developed in the future,” explains Bañuelos. The research underscores the importance of supporting research into rare diseases, as understanding the underlying mechanisms is the first step towards finding effective treatments.
Clinical Trial Underway: GAIN-CTNNB1
A Phase I/II open-label, single-dose clinical trial, GAIN-CTNNB1, is currently evaluating the safety, tolerability, and preliminary efficacy of an AAV9-based gene replacement therapy administered intracerebroventricularly to paediatric patients with CTNNB1 neurodevelopmental syndrome [1].
Source: EurekAlert!, news-usa.today, news-medical.net