Developing Novel Drug Strategies for the Treatment of Fragile X Syndrome by Functional Screening of Human Pluripotent Stem Cell Models
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability. FXS occurs due to epigenetic silencing, or non-expression, of a specific gene, FMR1. The goal of this project is to identify and test new drugs using human stem cells with the ability to induce re-expression of FMR1 and reverse FXS symptoms and effects. This proposal has 3 aims: 1. Establish baseline levels of FMR1 expression and downstream targets in normal and FXS stem cells 2. Screen novel categories of drug compounds and 3. Establish organoids, a type of tissue culture, from FXS stem cells to perform anatomical validation of drug efficacy. The overall goal of the project is to develop novel prenatal or early postnatal strategies for treating FXS.
Fragile X Syndrome (FXS) is the most common form of genetically inherited intellectual disability. Unfortunately, most FXS treatments address the symptoms and not the cause of the disease, and hence are not very effective nor curative. In addition, the existing drugs used for treatment must be taken throughout life and may pose a financial burden on the patient and their families -especially low-income families and the healthcare systems of low-income countries. Diagnosis, treatment, and added lifestyle costs for families with children with FXS are devastating.
FXS is caused by the FMR1 gene being silenced and transcriptionally inactive (e.g., the protein encoded by the gene is not functionally produced). So far, mouse models have been the favoured system to study FXS and devise therapies. As the human FMR1 gene is only silenced in FXS, and the encoded protein would be normal if expressed, a potential therapeutic strategy may be to reverse the gene silencing to re-express the FMR protein and thus stop the FXS symptoms. In the mouse models, the FMR1 gene is mutated rather than repressed. Thus, these mouse models are not suitable for developing a gene reactivation approach of therapeutic intervention. The goal of this proposal is to identify and test new drugs using human stem cells (which have their FMR1 gene silenced) to induce re-expression of FMR1 and reverse FXS symptoms and defects. This project has three main components: 1. Establish baseline levels of FMR1 expression and downstream targets in normal and FXS stem cells 2. Screen novel categories of chromatin modifying compounds in FXS stem cells 3. Establish organoid tissue cultures from FXS stem cells to perform an anatomical validation of drug efficacy.
The expanded catalogue of epigenetic modifying compounds and strategies identified in this research project could be developed into novel strategies for therapies. Long term, the researchers hope that such novel prenatal or early postnatal therapies could increase the child’s prospects and their quality of life, and reduce the burden on families and society.
Banner image above: Human embryonic stem cells can be modified to model human diseases that can then be used to find drugs to potentially rescue a disease. The first human embryonic stem cells modified and taken from pre-existing embryos were from Fragile X Syndrome.
Human embryonic stem cells in culture can be modified to model human diseases and then be used to find drugs to potentially rescue a disease. Image: Lab of Prof Nissim Benvenisty
Haploid embryonic stem cells can be used to more easily model human diseases and identify therapeutic approaches and show causation. Image: Lab of Prof Nissim Benvenisty
These neurons, which are derived in vitro from human embryonic stem cells, can be used to study how the human brain develops and to model neurological disorders. Image: Lab of Prof Nissim Benvenisty
Embryoid bodies which are a 3D mass of human embryonic stem cells are useful models to start the development and formation of specific organs. Image: Lab of Prof Nissim Benvenisty
- The research is part of the Postdoctoral Excellence Programme.
- PEP fellow Dr Keith Gunapala is hosted by BRCCH-funded Principal Investigator Prof Verdon Taylor (University of Basel), in collaboration with Prof Nissim Benvenisty (The Hebrew University of Jerusalem).