Project: Exploration of OCNDS: Bridging Model Systems, Molecular Mechanisms, and Therapeutic Approaches

The project team at TGen C4RCD is constituted of specialists with an array of diverse expertise. Dr. Sampath Rangasamy is a Research Associate Professor at the Neurogenomics Division and TGen's Center for Rare Childhood Disorders (C4RCD). His research concentrates on elucidating the cellular and molecular mechanisms through the utilization of cell and animal model systems. His research aims to elucidate previously unidentified signaling pathways, innovative targets, and treatments for both rare and common diseases. Dr. Vinodh Narayanan serves as a Clinical Professor and the Medical Director at C4RCD. Dr. Narayanan concentrates his research endeavors on the advancement of innovative therapies and cures for childhood neurological conditions. Dr. Narayanan has identified a cohort of patients with OCNDS and in collaboration with Dr. Rangasamy he successfully collected skin biopsies to establish an OCNDS cell biorepository. Dr. Matt Huentelman serves as a Professor and Director of Neurogenomics Division at TGen. Dr. Huentelman's research interests center around the investigation of the “-omics” (genomics, transcriptomics, and proteomics) of neurological traits and disease. His laboratory’s overarching goal is to leverage findings in these disciplines to better understand, diagnose, and treat human diseases of the nervous system. Dr. Huentelman and Dr. Narayanan collaborated to identify the genetic factors underlying rare genetic disorders in pediatric populations at C4RCD. You can learn more about the TGen OCNDS Research Program here.

Grant Details:

Project funded for 2 years starting in 2020 for a total of $180,000.

Aims of Grant:

1. Establishment of Patient-derived Cell line Biorepository for OCNDS Research

The primary goal of this project is to establish a comprehensive cell biorepository for OCNDS caused by CSNK2A1 mutation. This repository will be centered around dermal fibroblast cell lines derived from patients and will serve as a foundational resource for both internal research and external scientific collaborations. The dermal fibroblast cell lines will also enable researchers to delve deeper into the underlying molecular mechanisms of OCNDS. Patient-derived cell lines will be made available for shipment to global collaborators for additional functional work, thus catalyzing international research efforts. By creating this biorepository, we aim to advance our understanding of OCNDS and accelerate the path to the development of effective therapies.

2. Defining the Disease-Specific Cellular Phenotypes in Patient-Derived Cell Lines from OCNDS

This research aims to comprehensively characterize cellular phenotypes unique to OCNDS using dermal fibroblasts and induced pluripotent stem cells (iPSCs). The objective is to identify specific cellular markers or functional characteristics that could serve as phenotypes for high-throughput drug screening and as targets for therapeutic intervention.

3. Elucidating Disease Mechanisms through Phenotypic Characterization of CSNK2A1 Mutations in Zebrafish Models

The research aims to dissect the functional implications of both wild-type and mutant CSNK2A1 mRNA expression in zebrafish embryos. Concurrently, the study will examine the phenotypic outcomes in zebrafish embryos treated with CK2-selective inhibitors to assess their similarity to those induced by mutant CSNK2A1 expression. Through these approaches, the research seeks to illuminate the underlying disease mechanisms associated with CSNK2A1 mutations. Additionally, we will define the impact of different CSNK2A1 mutations on their ability to generate distinct phenotypes, thereby providing more informative data for developing an enhanced preclinical model system that can be sued for drug screening.

Published Results from this Grant to Date:

Preliminary Results posted on BioRXiv:

biorxiv.org/content/10.1101/2024.01.09.574075v1

Dominguez et al., 2021. Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity. Human Genetics 140:1077-1096.

Link to Research Explained

Belnap, N, Price-Smith, A, Ramsey, K, et al. Inherited CSNK2A1 variants in families with Okur-Chung neurodevelopmental syndrome. Clinical Genetics. 2023; 1-3. doi:10.1111/cge.14408

Link to Research Explained