Xiaoyu Chen Lab

Alternative splicing allows a single gene to produce multiple transcripts, efficiently and exponentially enhancing protein diversity, and could drive species difference and tissue diversity. We previously showed that, early in human development, the CACNA1C gene predominantly expressed the exon 8A isoform, and switched to the exon 8 isoform, a transition that is regulated by the splicing machinery. The Timothy syndrome-associated variant in CACNA1C significantly enhances the 8A isoform contributing to disease progression. We hypothesized that switching expression from exon 8A to exon 8 could serve as a therapeutic strategy. Through antisense oligonucleotide (ASO) “walking” screening in Timothy syndrome brain organoids, we identified candidates that reduced exon 8A and corrected the disease-related calcium channel defects. These ASOs also rescued cortical interneuron migration in organoids and, after in vivo transplantation, showed functional rescue in our model systems. We aim to apply similar approaches to a wide array of rare pediatric neurological disorders.

While current organoid technologies effectively model early stages of brain development, they are limited in their ability to capture later-onset disease. To address this, one branch of our research focuses on improving human neural models by enhancing neuronal maturation and reproducibility.

As we develop organoid systems that are more mature and stable, we can extend human-based modeling past prenatal developmental stages and begin to investigate neurological disorders that emerge in childhood.

A central focus of our lab is to translate mechanistic insights into therapeutic strategies. We are advancing ASO strategies to correct abnormal RNA splicing and counteract gain-of-function disease variants. ASOs have demonstrated clinical success in disorders such as spinal muscular atrophy, and their established safety profile makes them a promising platform for treating rare neurological diseases.

Our group is also looking into delivery approaches, including AAV-based vectors, to achieve stable gene modulation in the central nervous system. We are working to design and test ASO and viral constructs directly in human brain organoid models before moving toward preclinical studies, allowing us to pinpoint the most effective and safest strategy for each genetic background.

Our lab is part of the Center for Pediatric Neurodegenerative Research (CPNDR) within the Pediatric Translational Neuroscience Initiative (PTNI) at St. Jude, which fosters close collaboration across bench research and clinical teams. We work alongside colleagues studying childhood epilepsies and other neurodevelopmental disorders to refine disease models and evaluate emerging therapeutic strategies.

This collaborative network, combined with the exceptional resources and multidisciplinary environment at St. Jude, empowers our lab to advance the discovery and development of new treatments for rare neurological diseases.