JUL 13, 2018 1:49 PM PDT

Pharmacological Strategy Attempts To Treat Multiple Symptoms of Fragile X

WRITTEN BY: Nouran Amin

Recent research in a mouse model of fragile X syndrome (FXS), scheduled for publication in Neuropsychopharmacology, shows that a pharmacological strategy can reduce multiple behavioral and cellular deficiencies in the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

When a compound, by the name GSK6A, was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, symptomatic behaviors were alleviated including impaired social interactions and decision making, displayed by individuals with fragile X syndrome.

Results showed that treatment with GSK6A, an inhibitor of a cellular signaling enzyme called p110β form of PI3 (phosphoinositide-3) kinase, may serve as a logical strategy for treating cognitive and behavioral problems in fragile X syndrome; the efficacy, of course, would be evaluated in human clinical trials.

"Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, 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 effective treatments are available for fragile X syndrome that are targeted to the disease mechanism," Gross says. "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."

To ensure that undesirable side-effects of the pharmacological strategy do not appear, the researchers are first planning long-term animal studies on p110β inhibitors in fragile X syndrome.

1 in 3000 males and 1 in 6000 females are affected with Fragile X and females often have milder symptoms. Affected children may display intellectual disability with a delay of milestones such as speech. They may also feature autism-like features including impaired social skills, gaze aversion/social anxiety, hyperactivity and repetitive behaviors.

FXS is a result the silencing of a single gene, FMR1, which prevents the production of an RNA binding protein known as FMRP. FMRP manages the production of several proteins at synapses, the sites of communication between neurons.

In the current study, short-term treatments are only considered which covers one or two injections. For one experiment, mice were treated for 10 days, which normalized their densities of dendritic spines present in the hippocampus. Synaptic structures are overabundant in the absence of FMRP in animals and humans with FXS.

"It is likely that PI3 kinase—in its various forms—needs to be kept in a tight balance at the synapse," 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. We can't use mouse behavioral tests alone to understand a drug's effects," Bassell says. "It is critical to have molecular, cellular and neurophysiological phenotypes, which we and others do."

Source: Journal of Neuropsychopharmacology, Science Daily, Medical Xpress


About the Author
Doctorate (PhD)
Nouran is a scientist, educator, and life-long learner with a passion for making science more communicable. When not busy in the lab isolating blood macrophages, she enjoys writing on various STEM topics.
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