Mavoglurant (AFQ056), a candidate for the treatment of fragile X syndrome (FXS), restored functionality in sensory networks but failed to do so in a cognition-related brain region in a mouse model of the disease, recent study shows.
The research, “Inhibiting mGluR5 activity by AFQ056/Mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice” was published in NeuroImage.
Glutamate is the main excitatory brain chemical messenger (also known as neurotransmitter) in the central nervous system, which includes the brain and the spinal cord.
Abnormal signaling via a type of glutamate receptor called metabotropic glutamate receptor 5 (mGluR5) has been implicated in the disease mechanism of fragile X syndrome. Preclinical studies have shown that mavoglurant, a selective mGluR5 blocker being developed by Novartis, restores normal neuronal architecture and social behavior in an FXS mouse model.
Mavoglurant was also tested in large-scale clinical trials (NCT01357239, NCT01253629), but failed to show effectiveness in fragile X patients. More recently, results from two open-label extension studies in fragile X adolescents (NCT01433354) and adults (NCT01348087) suggest mavoglurant is safe and well-tolerated in the long term and eases patients’ symptoms (in more than 75% of participants).
Studies using resting state (when an explicit task is not being performed) functional magnetic resonance imaging (fMRI) have shown changes in neural networks among fragile X syndrome patients. Neuroimaging evidence also suggests alterations to the microstructure of the brain’s white matter. The latter consists of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter. The condition of the fibers influences the way the brain processes information.
Investigators from ETH Zürich in Switzerland have previously shown that a fragile x mouse model (called the Fmr1-/y mouse) had reduced functional brain connectivity and abnormal white matter, which correlated to what has been observed in human patients.
Neuroimaging seems to be a useful detector of fragile X-related functional changes. “Yet to date it is unknown whether MRI connectivity measurements are suited to map changes caused by interventions targeting the receptor level and, particularly, mGluR5 activity since no drug-interventional study has been performed using brain connectivity as primary outcome to score drug efficacy,” researchers said.
Now, Swiss researchers investigated whether resting state functional MRI could easily detect changes triggered by mGluR5 blockade.
Fragile X mice were randomly assigned to receive mavoglurant-spiked food pellets or standard rodent chow. Three weeks later, researchers assessed the animals’ cognition in the form of general sociability and interest in social novelty using the three-chamber test.
Two weeks after that, and still under treatment, mice underwent MRI so that scientists could examine the animals’ brain structure and functional connectivity.
Fragile X animals showed impaired social behavior (as measured by nose-to-nose contacts in the three-chamber test) and reduced connectivity in three main functional networks: somatosensory — related to sensing touch, temperature and the body’s position in space; temporal associative — involved in the recognition and identification of stimuli; and anterior-posterior cingulate — related to emotion and cognition.
Animals’ brain network layout was also significantly altered as scientists reported reduced local and global efficiency and increased neural path length. These functional abnormalities were accompanied by structural white matter changes.
Importantly, mavoglurant rescued temporal associative and somatosensory networks’ connectivity but failed to do so in the anterior-posterior cingulate network. Moreover, treatment did not improve sociability, social novelty interest and white matter structure.
Although animal models are useful tools in biomedical research, many times the effects observed in them cannot be translated into the clinic.
Although mavoglurant seems promising in restoring brain connectivity in FXS-related affected areas, these results demonstrate that such reversal was not reflected in animals’ behavior. This reflects the challenging nature of translating results from molecular biology experiments to behavioral ones and ultimately, from mice to humans.
Nonetheless, researchers believe that resting state fMRI “is sufficiently sensitive to pick up system-level changes after the pharmacological inhibition of mGluR5 activity.” However, their results “also show that the effects of mavoglurant are confined to specific networks, suggesting that behavioral benefits might be restricted to narrow functional domains.”