The lead collaborators have developed a small molecule inhibitor (BPN14770) of phosphodiesterase-4D (PDE4D). In FXS, large expansions of CGG repeats within the FMR1 gene result in its silencing and subsequent loss of the encoded protein. This protein product, FMRP, plays a regulatory role in the brain, suppressing the translation of mRNA important for synaptic function. Loss of FMRP results in decreased production of cAMP, over-expression of otherwise tightly-regulated genes, and synaptic dysfunction characteristic of FXS. Modulation of cAMP signaling through PDE4 inhibition had previously been tested in fruit fly models of FXS, showing an ability to rescue behavioral and structural phenotypes. The FRAXA Research Foundation tested BPN14770 in mouse models of FXS, showing increases in behavioral activity and social interaction, as well as restoration of brain cAMP levels. The team is collaborating on the completion of the following studies on BPN14770: - IND-directed toxicology in juvenile rats with reproductive toxicity assessment

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National Center for Advancing Translational Sciences
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