Identify Neuronal Signatures That Distinguish FXS Patients with Distinct EEG Phenotypes
Abstract
FY21 PRMRP Topic Area: Fragile X The proposed project addresses several Areas of Encouragement for Fragile X Syndrome (FXS), specifically development of a preclinical model that is representative of human FXS, research to advance the understanding of pathophysiology of FXS, and identification of novel targets and testing novel or existing therapeutics for FXS. Comprehensive Overview of the Proposed Research Project: FXS is the most common inherited cause of cognitive disability and the highest single gene cause of autism. Therefore, studying FXS will not only benefit those families affected by FXS but also those affected by autism, which affects 1 in 68 children. FXS results from inactivation of FMRP Translational Regulator 1 (FMR1) gene. Despite the identification of the gene and the establishment of multiple animal models, recent clinical trials of candidates have not succeeded. Therapies to help individuals with FXS have so far been ineffective due, in part, to the limitations of using animal models. Unlike the FXS mouse model, FXS patients have wide variation in clinical presentations and responses to treatment, despite having the same single gene mutation and absence of FMRP protein expression. This variability is likely a major contributor to the failures of FXS clinical trials. The causes of these variations are unclear and cannot be modeled using animal models. Therefore, establishing and characterizing human FXS models is critical for developing effective treatment. We propose to use human neurons derived from blood cell-derived stem cells to study how FXS neurons function differently from unaffected individuals, how FXS neurons differ among FXS individuals, and how we can design cost-effective clinical drugs and test drugs using these cells. Our collaborative group includes a clinician (Dr. Craig Erickson) who treats FXS patients and discovered that FXS patients exhibit significant differences in their brain electrical activities measured using a non-invasive method called electroencephalogram (EEG). He has also found that FXS patient with differences in EEG respond to clinical trial drugs differently. The project leaders of this proposal (Zhao and Bhattacharyya) have already generated stem cells from the blood of FXS patients with different EEG patterns and control individuals identified by Dr. Erickson. In our preliminary studies, human FXS neurons derived from these stem cells show differences in their features and activities. In the proposed project, our multidisciplinary team of scientists will use these neurons to identify signatures corresponding to differential EEG found in FXS patients and identify potential causes of these differences. Together, we propose to link the electrical properties in patients’ brains to the function of neurons in a culture dish to identify differences and potential targets of therapeutics. This project will have a high impact on the FXS field, both immediately and in the long run. Both the FY21 PRMRP and 2019 National Institutes of Health (NIH) Strategic Plan have indicated that development of a preclinical model that is representative of human FXS is a priority area of research. However, a missing piece of currently funded NIH FXS centers is the investigation of widespread severity and differential drug responses among FXS individuals. Our project will fill this gap. In addition, changes in brain electrical activity have been reported in patients with neuropsychiatric conditions, including autism. The outcome of project will benefit not only FXS but also other brain diseases on the PRMRP priority list.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210622
Entities
People
- Anita Bhattacharyya
Organizations
- United States Army
- University of Wisconsin–Madison