New Therapeutic Strategy Minimizes Fragile X Cognitive, Behavioral Defects in Mice

A new pharmacological strategy was able to minimize many cognitive and behavioral defects in mice with fragile X syndrome.

Researchers now believe this may be a promising therapeutic strategy for this disease and other brain disorders.

The findings from the study, “Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model,” recently published in Neuropsychopharmacology, were presented at the 16th NFXF International Fragile X Conference, held in Cincinnati, Ohio.

Fragile X syndrome is the most frequent single genetic cause of autism spectrum disorder (ASD). Children affected by the disease often exhibit austism-like features, including impaired social skills, hyperactivity, and repetitive behaviors, together with intellectual and developmental disabilities, such as speech.

Fragile X is caused by mutations in the FMR1 gene, which provides instructions for making an RNA binding protein called fragile X mental retardation protein (FMRP).

FMRP is present in many tissues, including the brain, testes and ovaries. In the brain, it is known to control the production of several proteins at the synapse — the region where nerve cells communicate with each other.

Several brain disorders, including fragile X, have been associated with defects in the phosphoinositide 3-kinase (PI3K) pathway, a biochemical cascade that can affect complex behaviors when abnormally activated at synapses.

In theory, this means that developing inhibitors to target PI3K signaling could have a therapeutic effect over fragile X and other brain disorders. However, this may not be that straightforward, because PI3K is essential for other cellular processes, and inhibiting the whole signaling cascade could have serious adverse side effects.

Researchers looked for selective inhibitors that could specifically block overactive components of the PI3K pathway, while leaving other components untouched. They found that selective inhibitors targeting specific isoforms of PI3K could be a viable therapeutic option for fragile X. An isoform is a functionally similar protein that has a close but not identical amino acid (the building blocks of proteins) sequence.

Lack of the FMRP protein increased the levels of p110β, a catalytic isoform of PI3K, in a mouse model and in cells isolated from fragile X patients.

“It is likely that PI3 kinase, in its various forms, needs to be kept in a tight balance at the synapse,” Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine, said in an Emory news release.

“Too much or too little can tip things into a suboptimal zone, especially for complex behaviors,” Bassell added. “We think targeting the excess p110β in FXS can restore signaling between upstream and downstream defects linked to the absence of FMRP.”

Using a novel, specific inhibitor for p110β, called GSK6A, researchers found the compound significantly improved cognitive and behavioral symptoms associated with the disease, including impaired social interactions and inflexible decision making, in two distinct mouse models unable to produce FMRP.

Moreover, short-term treatment (one or two injections of the compound) over the course of 10 days normalized the densities of dendritic spines — synaptic structures that are overabundant in the absence of FMRP in mice and in humans with fragile X — in the hippocampus of these animals.

Researchers are confident that GSK6A or a similar compound could be a viable treatment option for patients with fragile X and other brain disorders. However, such a hypothesis would have to be assessed in future 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,” Bassell said.