Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model

Abstract

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.

Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model

“…Therapeutic value of correcting the altered PI3K-Akt-S6K1 signaling in FXS is strongly suggested by that genetic removal/reduction of S6K1, PIKE, and p110ß subunit of PI3K can rescue the elevated overall protein synthesis and multiple behavioral abnormalities in Fmr1 KO mice 18,28,35 . A more recent study showed that systemic injection of a novel p110β-specific inhibitor GSK2702926A, a similarly structured compound of which is under investigation in a cancer clinical trial, rescues cellular and behavioral abnormalities in Fmr1 KO mice 46 . To realize therapeutic value of targeting the PI3K-Akt-S6K1 signaling cascade, a significant advancement is to find a clinically suitable approach to effectively dampen PI3K-Akt-S6K1 activity in FXS.…”

“…Lack of absolute efficacy is common for drugs used for complex neurological disorders. It is noticed that targeting ERK1/2 or PI3K by lovastatin, metformin, and GSK2702926A rescues some but not all symptoms 19,39,46 . Such limitation may be due to multiple pathological alterations in FXS; combinatorial targeting multiple disease factors represents an emerging idea to achieve more robust therapeutic outcome 47 .…”

Kinase pathway inhibition restores PSD95 induction in neurons lacking fragile X mental retardation protein

“…In contrast, treatment with S6K1 inhibition may be more beneficial by specifically targeting abnormal protein synthesis (47). Another recent study found that inhibition of the specific PI3K isoform p110β can ameliorate FXS behavioral symptoms (50), suggesting that specific inhibition of p110β-driven mTOR activity could also be more beneficial than inhibiting all mTOR signaling.…”

Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model

“…Therapeutic value of correcting the altered PI3K-Akt-S6K1 signaling in FXS is strongly suggested by that genetic removal/reduction of S6K1, PIKE, and p110ß subunit of PI3K can rescue the elevated overall protein synthesis and multiple behavioral abnormalities in Fmr1 KO mice 15, 39, 48 . A more recent study showed that systemic injection of a novel p110β-specific inhibitor GSK2702926A, a similarly structured compound of which is under investigation in a cancer clinical trial, rescues cellular and behavioral abnormalities in Fmr1 KO mice 49 . To realize therapeutic value of targeting the PI3K-Akt-S6K1 signaling cascade, a significant advancement is to find a clinically suitable approach to effectively dampen PI3K-Akt-S6K1 activity in FXS.…”

“…Lack of “absolute efficacy” is common for drugs used for complex neurological disorders. It is noticed that targeting ERK1/2 or PI3K by lovastatin, metformin, and GSK2702926A rescues some but not all symptoms 40, 41, 49 . Such limitation may be due to multiple pathological alterations in FXS; combinatorial targeting multiple disease factors represents an emerging idea to achieve more robust therapeutic outcome 50 .…”