Researchers at MIND Institute at UC Davis and Rush University Medical Center have found that mavoglurant, an experimental drug known as an mGluR5 negative modulator, can positively modify a key characteristic behavior in individuals with fragile X syndrome (FXS).
The results of the study, published in PLOS ONE, present the first clinical evidence that this class of drugs improves eye gaze behavior and alters reactivity to faces in patients with FXS.
Gaze avoidance, a hallmark feature of FXS, reflects social anxiety and interferes with social engagement and social-emotional development. Individuals with FXS make less eye contact, look less at the eye region of human faces and have greater pupil reactivity to emotional faces, when compared to typically developing individuals.
“Social anxiety is one of the most important manifestations of FXS. Gaze avoidance is a pretty good indicator of this social anxiety or avoidance, and that can be measured with an eye tracker,” said David Hessl, clinical professor in the Department of Psychiatry and Behavioral Sciences and a researcher at the MIND Institute. “One issue facing our field is the lack of validated biomarkers that can help us determine whether a treatment has engaged its target and is having any effect on behavior. Sensitive laboratory-based biobehavioral measures can be useful tools for detecting targeted treatment-related responses.”
Using an infrared binocular eye tracker, the researchers collected gaze pattern data of 57 patients with FXS at baseline and following three months of blinded treatment. Participants were between 12 and 45 years old, had an IQ below 70, and were randomly assigned to receive either one of three doses of mavoglurant (25mg, 50mg, or 100mg) or placebo.
The study found that patients treated with mavoglurant looked significantly more at the eye regions of the human faces relative to baseline and compared to those treated with a placebo. Also, participants on the treatment had greater pupil dilation as a sign of reactivity to faces relative to baseline and to participants taking the placebo.
"Mavoglurant appears to target a core problem in FXS patients," said Elizabeth Berry-Kravis, pediatric neurologist at Rush University Medical Center and co-author of the paper.
"This type of drug has been one of the most studied ever in preclinical models of developmental disability," she added. "It has produced improvement in the fragile X mouse, fly and rat models. Yet these findings could not be extrapolated to human trials. The findings in this study suggest the drug is targeting the brain and has an effect on FXS. The eye tracking test may be a biomarker indicating that the trials completed thus far may not be looking at the right outcomes."
Earlier clinical trials with humans failed to show improvement in teenagers and adult patients with FXS. With a series of failures to show significant behavioral improvement over placebo in clinical trials, this study provides support that mavoglurant can be a promising drug that may impact a core behavioral feature of FXS and can encourage researchers to look at different trial designs.
“These objective indicators serve as biomarkers that appear to be sensitive to the treatment,” added Hessl. “This by itself is encouraging on the biomarker development side, and hopefully will open others’ eyes to the possibility that the mGluR theory and modulation might still be clinically and scientifically relevant for people with fragile X.”
Berry-Kravis is currently leading a study funded by NIH through the NeuroNext network to evaluate the effects of Mavoglurant on language learning in 3-6-year-old kids with fragile X in a new trial design. Hessl is leading the eye tracking portion of this trial.
“The eye tracking study supports the plan in our NeuroNext study to evaluate the drug effects on learning, also a core feature of FXS, in children who may have more potential for improving the learning ability relative to older patients.”
FXS is an X chromosome-linked genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. FXS occurs in approximately 1 in 4,000 males and 1 in 8,000 females and is associated with significant reduction or complete absence of Fragile X Mental Retardation Protein (FMRP).
The manifestations of the disorder vary and consist of physical features, intellectual disability, autism or autistic-like behaviors. It also includes high rates of anxiety and social withdrawal, inattention and distractibility, disinhibition and impulsivity, hyperactivity, aggression and self-injury.
This work was supported by Novartis Pharma AG, Basel, Switzerland and the MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125).
Other UC Davis researchers included Danielle Harvey, Stephanie Sansone and Randi Hagerman. Additional contributors are Crystal Crestodina, Jamie Chin and Reshma Joshi at Rush University Medical Center.