Modeling Fragile X Syndrome Using Human Brain Organoids
Abstract
The proposed project addresses the Peer Reviewed Medical Research Program topic area of Fragile X. Fragile X syndrome (FXS, OMIM#300624) is the most common inherited form of intellectual disability and a leading genetic cause of autism spectrum disorder (ASD). A DNA repeat sequence expansion within part of the FMR1 gene has been identified as the most prevalent cause of FXS. This expansion beyond 200 repeats, referred to as the full mutation, leads to the gene being shut off, and, as a result, the fragile X mental retardation protein (FMRP) is not made. FMRP is responsible for regulating when other proteins are made in neurons. When FMRP is not made, the levels of other genes are not properly regulated, and many of these genes are autism-linked genes. Human-induced pluripotent stem cells (iPSCs) are able to generate any kind of cell type. Human iPSCs could be used to model human development and disease, screen for therapeutic drugs, and develop cell replacement therapies. Conventionally, iPSCs have been studied in a two-dimensional monolayer culture. The lack of three-dimensional properties of cell assembly limits the capabilities of the culture to truly resemble biological systems. Three-dimensional aggregate culture of iPSCs has evolved from embryoid body cultures, quite faithfully following human organ development. This innovative platform to investigate human brain development in a dish can be used to produce ?mini-brains? where neurodevelopment can be studied. N6-methyladenosine (m6A) is a mark that can be seen on some genes. Recent studies have shown that changes in these m6A marks could lead to neurodevelopmental defects in mice and in the mini-brain organoid model. These marks have been shown to be associated with autism-linked genes and with the targets of FMRP. In addition, these m6A marks are more frequent in humans compared to mouse models. Previously, multiple drug trials have been done in FXS patients. Targets that were identified as effective in mice did not have an effect in FXS patients. We will make mini-brains from human FXS iPSCs and normal iPSCs to study which genes are affected. From these human-specific targets, we have the potential to identify druggable targets for both FXS and autism in general.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910068XX0
Entities
People
- Emily Allen
Organizations
- Emory University
- United States Army