Funded Research

Principal Investigator: Heike Rebholz, PhD Laboratory of Signaling Mechanisms in Neurological Disorders Institut de Psychiatrie et Neuroscience de Paris (INSERM) Co-funded by the CSNK2A1 Foundation and Syngap Research Fund (SRF) Overview This collaborative grant brings together two rare disease communities, Okur-Chung Neurodevelopmental Syndrome (OCNDS) and SYNGAP1-related disorders, to investigate a shared biological mechanism that could help explain overlapping symptoms such as seizures, learning difficulties, and autism spectrum features. The project focuses on CK2-mediated phosphorylation of SYNGAP1. Scientific Background SYNGAP1 is a critical postsynaptic protein that regulates neuronal signaling and plasticity. Its proper function depends on phosphorylation, a chemical “switch” that modifies how proteins behave. Dr. Rebholz’s team has discovered that phosphorylation of SYNGAP1 is markedly reduced in brain tissue from mouse models of OCNDS, where mutations in the CK2α subunit (CSNK2A1) lead to reduced kinase activity. By identifying how CK2 regulates SYNGAP1, this project aims to uncover a convergent mechanism between OCNDS and SYNGAP1 disorders, providing insight into why these syndromes share clinical features and pointing toward possible therapeutic strategies that could benefit multiple neurodevelopmental disorders. Specific Aims Aim 1: Identify phosphorylation sites. Determine which SYNGAP1 sites are directly phosphorylated by CK2 and whether OCNDS-linked CK2 variants impair this activity. Aim 2: Define biological consequences. Examine how phosphorylation affects SYNGAP1 localization in neurons, its role in synaptic signaling, and regulation of Ras/Rap pathways. Aim 3: Assess in vivo effects. Introduce phospho-mutant SYNGAP1 into wildtype mice to test impacts on seizures, repetitive behaviors, and memory. Significance By bridging two gene communities, this study embodies the Foundation’s mission to accelerate research and therapeutic development through collaboration. If CK2-mediated phosphorylation of SYNGAP1 proves to be a shared pathogenic mechanism, it could open the door to cross-disorder treatment strategies that target common pathways rather than individual genes. Funding This project is supported with a total of $160,000 in funding over two years (2025–2027), with 85% funding by SRF and 15% funding from CSNK2A1 Foundation.

Lead Investigator: Dr. Miya St. John, BSc, MAppLing, MSpPath, PhD Grant Details: Project funded for 1 year starting in 2025 for a total of $33,735.05. Aims of Grant: Speech and language challenges have been reported in individuals with OCNDS, including delayed communication milestones, atypical oral-motor skills, significantly delayed literacy development, and non-specific ‘impaired speech ability’ as well as autism and autistic-features (see Chiu et al 2017; Okur et al 2016; Owen et al 2018). However, the communication profile remains poorly characterised. No studies to date have sought to examine speech and language in a systematic manner, nor used standardised or formal assessments to delineate between speech and language diagnoses (which is an often misunderstood but clinically important distinction). Currently, our understanding of this condition lacks a clear delineation between motor-based speech disorders (e.g., speech apraxia) compared to cognitive-linguistic impairments. These distinctions are critical for patient care, as without accurate diagnoses, parents and clinicians remain unsure about what therapies to implement, or further may implement incorrect therapies, resulting in wasted time, resources, and money and without positive outcomes. Our research aims to characterise the speech and language abilities of individuals with CSNK2A1 variants, and in doing so will: provide a definitive diagnoses, prognoses and treatment planning guide for families and clinicians, investigate whether there are clinical differences corresponding to variant location (i.e., genotype-phenotype correlation) to more specifically inform prognosis, and use collected data to delineate optimal speech and language outcome measures to be used in future clinical trials

Lead Investigator: Vishnu Cuddapah, MD, PhD, Assistant Professor, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Baylor College of Medicine Grant Details: Project funded for 1 year starting in 2025 for a total of $70,025. Aims of Grant: Sleep and circadian rhythm disturbances are common in individuals with Okur-Chung Neurodevelopmental Syndrome (OCNDS), yet their underlying mechanisms remain poorly understood. Studying these phenotypes can provide critical insights into the role of CSNK2A1 in neurodevelopment and offer potential therapeutic targets to improve sleep-related symptoms in individuals with OCNDS.  This project aims to further characterize sleep and circadian phenotypes in individuals with OCNDS through ongoing clinically relevant questionnaires, developing Drosophila (fruit fly) models harboring 7 distinct CSNK2A1 variants to assess their impact on sleep and circadian rhythms, and screening a curated list of compounds to identify drugs that may reverse sleep and circadian phenotypes. By validating drug candidates in a high-throughput system, we aim to accelerate the path toward preclinical studies, complementing ongoing research in mouse and iPSC models. The findings will contribute to a deeper understanding of OCNDS pathophysiology and inform future therapeutic strategies.

Lead Investigator: Abdelhalim Loukil, PhD, Sanford Research Institute Grant Details: Project funded for 1 year starting in 2025 for a total of $60,013. This grant was funded in collaboration with the Orphan Disease Center at the University of Pennsylvania Perelman School of Medicine's Million Dollar Bike Ride . The CSNK2A1 Foundation raised $30,013 and the Orphan Disease Center contributed a $30,000 match. Aims of Grant: The proposed project aims to investigate how mutations in the Csnk2a1 gene contribute to a rare genetic disorder called OCNDS, which causes speech difficulties, motor impairments, and cognitive issues. We will look at how these mutations affect the function of primary cilia, which are tiny hair-like structures in cells that play an important role in cell communication and brain development. By studying both mouse models and patient cells, we will identify the specific molecular changes in cilia caused by the gene mutation and their effects on brain development. This proposal will help us better understand how ciliary malfunction contributes to developmental difficulties in OCNDS. Additionally, we hope to uncover novel therapeutic targets by identifying the molecular pathways affected by the mutation. Our ultimate goal is to provide insights that could lead to potential treatments for the neurological challenges seen in OCNDS.

Lead Investigator: Unravel Biosciences  Unravel Biosciences is the first rapid prototyping therapeutics company, integrating AI systems biology computation with rapid in vivo screening and clinical validation of discovered targets with unprecedented efficiency. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases. Unravel's platform has led to four clinical trials starting in 2024. Unravel's platform developed RVL002, a first-in-class new small molecule targeting mitochondrial metabolism, and RVL027, a molecule targeting a novel mechanism to treat dystonias. The rareSHIFT™ program provides platform access to foundation and biotech partners to accelerate and clinically derisk therapeutics. unravel.bio and rareshift.org Grant Details: Project funded for 1 year starting in 2024 for a total of $43,000. Aims of Grant: Unravel will collect nasal swabs from 10 families (swabs from individuals with OCNDS and a sex-matched relative control, such as a parent or sibling). They will generate RNA sequencing data from the nasal swabs that will be used to predict drugs and therapeutic mechanisms using the BioNAV™ platform. Resulting predictions will be compared against results of the mouse drug prediction task to further narrow the predicted drugs for subsequent screening. This will generate the first primary clinical molecular dataset for CSNK2A1. For this pilot grant, individuals with the most common mutation in CSNK2A1 (K198R) will be analyzed.

Discover mouse models of OCNDS by Dr. Heike Rebholz at CSNK2A1 Foundation & learn about CK2 protein mutations' impact on brain cell communication & treatment advancements.

Characterization of CSNK2A1 disease-causing variants in 2D neurons by Dr. Matt Huentelman at CSNK2A1 Foundation. Research grant aims to understand genotype-phenotype relationships for potential therapeutic insights.

Explore the project on isogenic control iPSC models for OCNDS by CSNK2A1 Foundation. Contact CSNK2A1 for more info.

Explore our project on OCNDS mouse models for research. Learn more!

Explore the computational characterization of CSNK2A1 variants in OCNDS | Led by Dr. Isabel Dominguez, this research aims to understand genetic mutations' impact on neurodevelopmental disorders. Learn about efforts in finding a cure for Okur-Chung Neurodevelopmental Syndrome.