Jessica is a first-year medical student, University of California Davis School of Medicine, supervised by Dr. Paul Hagerman, Distinguished Professor of the Department of Biochemistry and Molecular Medicine and MIND Institute UC Davis School of Medicine
Transcriptional Gene Silencing of FMR1 as a Treatment for Fragile X-Associated Tremor/Ataxia Syndrome
Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by an abnormal Fragile X (FMR1) gene that produces high levels of the Fragile X protein (FMRP) that leads to neurodegeneration. We propose a gene therapy to knock out the abnormal FMR1 gene and, in follow-on work, add a coding cassette comprising a mini-promoter and FMRP coding region.
The goal of my project is to identify the RNA sequence(s) that can successfully target and silence the abnormal FMR1 gene. To do this, I package multiple RNA candidates into small (nano)particles that are then delivered to fibroblast cells. After the fibroblasts have grown for 1 week, 4 weeks, and 8 weeks, I will quantify how much FMR1 RNA and protein are produced by the fibroblasts. This allows us to determine how effective a given candidate sequence is in silencing the FMR1 gene. From my results, we will select the candidate RNA to be used in subsequent studies to silence FMR1 in rat and rhesus models. Our long-term goal is to develop a genetic therapy that will prevent neurodegenerative difficulties in patients with FXTAS by targeting the expression of the abnormal FMR1 gene.
In their own words:
“During my first year of medical school, I worked with Dr. Randi Hagerman, helping out with clinical trials and shadowing her through patient visits. This summer through the RJH NFXF Summer Scholar Program, I had the amazing opportunity to work under Dr. Paul Hagerman and see the translational science side of research — something that is often difficult to do during the school year.
“This summer, I am proud to have created a pipeline for identifying and screening small transcriptional gene silencing-RNAs (sTGSs) for gene therapy in Fragile X and FXTAS. Furthermore, I was able to identify two potential sTGSs that could lead to long-term suppression of abnormal FMR1 gene.
“Thank you NFXF for providing a platform to share my work and for supporting my aspirations of becoming a physician in academic medicine. I am so excited to continue working in the field of Fragile X among amazing mentors and leaders of their field!”
—Jessica Tang, University of California Davis School of Medicine