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Scientists report that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders. The study (“Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model”) is published in Neuropsychopharmacology.

Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, 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,” write the investigators.

“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.”

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of FXS, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with FXS. 

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in FXS; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

“Our results suggest that p110β inhibitors can be repurposed for FXS, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, Ph.D., professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for FXS that are targeted to the disease mechanism,” adds Christina Gross, Ph.D., who collaborated with Dr. Bassell and works at Cincinnati Children’s Hospital and is assistant professor, department of pediatrics at the University of Cincinnati. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.” 

While the researchers are discussing clinical trials of p110β inhibitors in FXS, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. 

Fragile X syndrome is caused by silencing of a single gene, FMR1, preventing production of an RNA binding protein, FMRP. FMRP controls the production of several proteins at synapses, the sites of communication between neurons. 

The mouse studies described in the current paper cover short-term treatment (one or two injections). In one experiment in which mice were treated for 10 days, it normalized the densities of dendritic spines in the hippocampus, synaptic structures that are overabundant in the absence of FMRP in the mouse model and in humans with FXS.

“It is likely that PI3 kinase – in its various forms — needs to be kept in a tight balance at the synapse,” Dr. Bassell says. “Too much or too little can tip things into a suboptimal zone, especially for complex behaviors. We think targeting the excess p110β in FXS can restore signaling between upstream and downstream defects linked to the absence of FMRP.”

While PI3 kinase is an important cellular enzyme, Dr. Bassell emphasizes that p110β is just one of its four forms. The researchers showed that GSK6A is selective for p110β only, which indicates that it is less likely to be toxic; more investigation of potential toxicity is necessary.

The paper also includes tests on other biochemical measures such as regulation of protein synthesis in brain tissue slices, susceptibility to seizures triggered by sound, and behaviors such as grooming and nesting.

With respect to clinical trials, the fragile X community has been disappointed before, points out the research team. Based on studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures; the ages of study participants and drug tolerance may have played a role.

“We can't use mouse behavioral tests alone to understand a drug's effects,” notes Dr. Bassell. “It is critical to have molecular, cellular and neurophysiological phenotypes, which we and others do.” He adds that models incorporating human neurons, derived from induced pluripotent stem cells, could be complementary.

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