Investigating the Feasibility of Gene Therapy for the Treatment of TBRS

About This Grant

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) often result from mutations in genes essential for brain development and function. Recent advances in gene replacement therapy have shown promise for rescuing molecular and behavioral deficits in mouse models, even when gene restoration occurs postnatally. However, the context and feasibility of gene replacement for specific disorders remain unclear. This project focuses on Tatton Brown Rahman Syndrome (TBRS), a rare NDD caused by mutations in DNMT3A, a gene critical for DNA methylation and neuronal development. TBRS patients exhibit intellectual disability, overgrowth, joint hypermobility, and seizures. In mice, loss of DNMT3A leads to altered neuronal differentiation and synaptic function, emphasizing its importance in early brain development. Kim will explore the potential for restoring DNMT3A function using innovative mouse models and gene therapy approaches. In Aim 1, Kim will employ spatial transcriptomics and single-nucleus RNA sequencing to assess how DNMT3A loss impacts cell type distributions and gene expression in the cerebral cortex and whether these changes can be reversed by restoring DNMT3A expression. In Aim 2, she will evaluate the feasibility of gene replacement therapy for TBRS using adeno-associated viruses (AAVs). These studies will address timing, delivery methods, and baseline efficacy of DNMT3A reinstatement in both tamoxifen-inducible and disease-relevant mouse models. This work will determine whether postnatal DNMT3A restoration can rescue molecular, cellular, and behavioral deficits associated with TBRS and provide a foundation for gene therapy strategies targeting NDDs. The findings will contribute to understanding the therapeutic potential of gene replacement, with implications for improving outcomes and quality of life for patients and families affected by TBRS and related conditions. This project will be conducted at Washington University in St. Louis, a phenomenal research environment that integrates cutting-edge genomic technologies, advanced imaging platforms, and expertise in neurodevelopmental disorders. The lab is supported by collaborations with leading researchers in mouse behavior, epigenetics, and computational biology, ensuring access to unparalleled resources and mentorship. This environment fosters innovation, collaboration, and rigorous scientific inquiry, creating the ideal setting to achieve the goals set forth by this proposal.