We are pleased to announce a continuation grant to Prof. Illana Gozes at Tel Aviv University to establish and comprehensively characterize a mouse model harboring the R292C point mutation in STXBP1. This variant is one of the pathogenic heterozygous mutations known to disrupt synaptic vesicle fusion processes and is clinically associated with early-onset epileptic encephalopathy, global developmental delay, autism spectrum features, and motor dysfunction.
Prof. Gozes is a leading molecular neuroscientist and Head of the Elton Laboratory for Molecular Neuroendocrinology at Tel Aviv University. Her research has produced foundational insights into neurodevelopmental and neuroprotective mechanisms, reflected in approximately 400 peer-reviewed publications, 40,000 citations, 125 patents, and major discoveries including ADNP and its active neuroprotective fragment, davunetide.
The initial R292C mouse colony was generated at the Institute of Molecular Genetics of the Czech Academy of Sciences in collaboration with the Gozes laboratory, through a previous grant we funded. This model is now being transferred to Israel to enable deeper mechanistic studies and to form the basis for translational therapeutic investigations.
Scientific Background
STXBP1 (syntaxin-binding protein 1) is a key regulator of synaptic vesicle exocytosis. The protein functions analogously to an orchestral conductor, ensuring the temporal precision and reliability of neurotransmitter release. Heterozygous pathogenic variants impair STXBP1 stability or function, resulting in reduced availability of the active protein and subsequent perturbations in synaptic communication.
This loss of function has broad pathophysiological implications, including:
- Impaired synaptic vesicle docking and fusion
- Altered cortical network synchrony
- Disrupted neurodevelopmental trajectories
- Increased susceptibility to seizures
- Deficits in learning, motor coordination, and social behavior
Studying these mechanisms requires in vivo systems that recapitulate developmental processes, neuronal circuitry, and behavioral phenotypes.
Objectives of the New Grant
1. Establishment of the R292C Mouse Colony in Israel
The project will rederive and expand the colony under controlled conditions to ensure genetic fidelity and reproducibility. This will provide a stable resource for local and international researchers.
2. Phenotypic and Molecular Characterization
The characterization phase will include:
- Developmental milestone assessment
- Behavioral profiling (motor, cognitive, social, and anxiety-related phenotypes)
- Electrophysiological recordings to evaluate synaptic transmission and network activity
- Molecular assays to quantify STXBP1 protein levels, stability, and downstream signaling pathways
These studies aim to delineate how the R292C mutation alters neuronal and circuit-level function across development.
3. Establishment of a Preclinical Screening Platform
Once phenotypic readouts are defined, the model will serve as a platform for evaluating therapeutic candidates, including:
- Small-molecule modulators
- Gene-expression–restoring strategies
- Peptide or protein replacement approaches
- Combinatorial therapies
This will enable both target-based and phenotype-based drug screening campaigns.
Collaboration and Model Distribution
Consistent with our commitment to open scientific collaboration, the R292C mouse model will be made available to additional academic and translational research centers.
Labs interested in mechanistic studies, biomarker development, or therapeutic testing are invited to collaborate or request access to the model once the colony is fully established.
For Rafa’s Moonshot full list of disease models click here.
Looking Ahead
The development of the R292C model in Israel expands the Rafa’s Moonshot disease-model portfolio and provides a critical tool for dissecting STXBP1-related pathophysiology. By integrating molecular, behavioral, and electrophysiological analyses, this project will advance our understanding of the disorder and accelerate the path toward targeted treatments.
This effort represents another step toward a comprehensive translational pipeline for STXBP1 disorders, integrating basic science, model development, and therapy discovery.
