Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.
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We thank Jeffrey Rymer, Nathan Petts, Joun Y. Lee, and Jingsheng Gu for technical assistance, and Emanuela Santini as well as all members of the Bassell, Gourley, and Gross labs for helpful discussions. This research was funded by NIH grants R21MH103748 (to C.G., S.L.G.) and 1U54HD082013 (to G.J.B.), a NARSAD Independent Investigator Award from the Brain and Behavior Research Foundation (to C.G.), two Summer Student Fellowships from the National Fragile X Foundation (to J.C.K., N.A.E.), the Cincinnati Children’s Research Foundation (to C.G.), and Children’s Healthcare of Atlanta (to S.L.G.). The Yerkes National Primate Research Center is supported by the Office of Research Infrastructure Programs/OD P51OD011132.