Reactivating the FMR1 Gene to Reverse Fragile X Syndrome

$90,000 FRAXA Research Grant for 2019

FRAXA has awarded $90,000 to Dr. Jeannie Lee and Dr. Hungoo Lee at Harvard Medical School and Massachusetts General Hospital. This team is targeting the root cause of Fragile X syndrome: a silenced single gene, called FMR1.

With a previous $180,000 grant from FRAXA Research Foundation and The Pierce Family Fragile X Foundation from 2016-2018, the team ran a series of studies aimed at reactivating FMR1. They found a method using combinations of drugs which spur the gene to produce its normal protein product. Using drug “cocktails” they are able to reactivate FMR1 in cells in their lab! Dr. Lee explains in this video.

Jeannie Lee, MD, PhD
Principal Investigator

Hungoo Lee, PhD
FRAXA Postdoctoral Fellow

Total Funding to This Lab to Date: $270,000

Harvard University Medical School
Massachusetts General Hospital

by Jeannie Lee, MD, PhD

Fragile X syndrome (FXS) is caused by expansion of CGG trinucleotide repeats in the FMR1 gene. The Fragile X “full mutation” – a very long expansion resulting in over 200 CGG repeats – causes  silencing of the FMR1 gene. Defining the mechanism of repeat expansion and gene silencing could pave the way for treatment through FMR1 reactivation.

With funding from FRAXA Research Foundation and The Pierce Family Fragile X Foundation, we have discovered a method that will reactivate the FMR1 gene by treating cells with a cocktail of small molecules, under a specific regimen in vitro (patent filing pending). Reactivation levels are significant at both the RNA and protein levels.

In human induced pluripotent stem (iPS) and embryonic stem (ES) cell lines from patients with Fragile X syndrome, the FMR1 gene is usually completely silenced. In our lab, we demonstrated de-repressed FMR1 gene transcription and an increase in the protein FMRP.

With the current grant, we are currently following up on this promising observation:

  1. We are repeating the experiment using different patient cell lines to rule out clonal and other technical artifacts.
  2. We are testing whether a similar reactivation can be observed in patient-specific neuronal cells.
  3. We are investigating the underlying mechanism to better define the reactivation process.

This project shows that we can reactivate a gene in single cells in the lab. Many issues remain to be understood; for example, it is not yet known if this strategy works with all cells or just a small subset of cells (clonal artifact). Much remains to be done. However, this is the kind of work that must be done to make a definitive cure for Fragile X to be a reality one day. Our ultimate goal is to translate this knowledge and advance this clinical candidate as a Fragile X treatment mechanism.

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