Screening 2,320 FDA-Approved Drugs for Potential Treatment of Fragile X

FRAXA Research Foundation has awarded a $90,000 grant to Principal Investigator Dr. Sean McBride and Postdoctoral Fellow Dr. Karen Joyce, at Rowan University, to screen all 2,320 FDA-approved drugs in the fly model of Fragile X syndrome. Drugs which show promise will be tested in more detail for the potential to treat Fragile X syndrome in humans.

$90,000 Grant

Sean McBride, MD, PhD
Principal Investigator

Karen Joyce, DVM
FRAXA Fellow

Rowan University
2018-2019 FRAXA Research Grant
$90,000 over 2 Years

by Sean McBride, PhD, and Karen Rowan, DVM

Our lab utilizes the model organism Drosophila melanogaster (fruit fly) to identify genes that can enhance or suppress social memory impairments in the Fragile X fly model. The protein products of these genes may be novel drug targets for treatment. We also use a long-term memory (LTM) paradigm that we developed previously to screen for molecules that can rescue LTM and social interaction.

In this project, using the fly model, we will perform an unbiased screen of 2,320 FDA-approved compounds. Unlike most Drosophila screens which use the eye phenotype or cell screens, we are testing the key phenotypes of interest, memory, and social interaction. Therefore, we are trading off speed of throughput in screening, to increase the specificity of identifying molecules that are effective in the fly model. Then, using the mouse model of Fragile X, we will test chronic treatment with the medications which show the most promise.

Fruit Flies as a Test Bed

The fly model is useful because of the exquisite conservation of intracellular signaling involved in memory formation, from flies to Aplysia to mice to humans. Memory formation is an extremely intricate process at the molecular signaling level, and it has been highly conserved throughout evolution. The phases of memory in invertebrates parallel the findings in mammals. A great example of this was first demonstrated by the laboratory of Ron Davis when he took the gene for the PDE-4 in the rat and was able to demonstrate that the rat gene functioned in the fly model and was able to compensate for a loss of function mutation in the same gene in Drosophila and rescue memory (Dauwalder and Davis, 1995).

Our lab has used the Fragile X fly to first demonstrate mGluR antagonists, lithium, PDE-4 inhibitors and metformin could rescue social and memory impairments (McBride et al., 2005; Choi et al., 2015; Monyak et al., 2016). Each of the findings has progressed to clinical trials.

Screening Over 2000 FDA-Approved Available Compounds

The current grant includes unbiased testing of all medications approved by the FDA and approved in Europe, as well as additional supplements and bioactive molecules. It is important to have a mixture of different compounds when considering repurposing medications or developing novel derivatives of current medications.

After the fly screen, we will further investigate any compounds of interest with a full characterization that will include:

  • testing multiple phases of memory
  • attention
  • sleep and circadian behavior
  • neuro-anatomical phenotypes
  • biochemistry and histology in the brain
  • developmental efficacy

We will prioritize characterizing positive hits in the fly model from the screen by looking at the molecules availability, ability to cross the blood brain barrier, and safety.

For any medication that looks promising in the fly, the next goal of our research is to advance to testing in the mouse model of Fragile X. True transformative discoveries for human disease go beyond identification of novel targets and begin testing in mammalian systems, so testing in the mouse model is an important step toward Fragile X clinical trials.

Explore Current Fragile X Research

FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.