Cellular-Specific Therapeutic Targeting of Inhibitory Circuits in Fragile X Syndrome

Studies have shown that the function of inhibitory networks is disturbed in Fragile X. This abnormality is not well understood but appears to be secondary to abnormalities in metabotropic glutamate and endocannabinoid systems. With a $90,000 grant from FRAXA, Dr. Molly Huntsman’s team examined how these networks interact and how inhibitory deficits can best be remedied.

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Auditory Dysfunction in Fragile X Syndrome in a Mouse Model of Fragile X

Elizabeth MCullough and Achim Klug

With a $90,000 grant from FRAXA, Dr. McCullagh and Dr. Achem Klug at the University of Colorado investigated whether auditory neural circuits are altered in Fragile X mice. They saw minor differences in these mice compared to B6 (control) mice in several measures of auditory acuity. Fmr1 mice had increased latency to the startle response for almost all conditions compared to B6 mice, suggesting altered timing to acoustic cues. These experiments show that, consistent with patient reports and anatomical/physiological data, the auditory system is altered in a mouse model of FXS, though with some potential compensation leading to a subtle behavioral impact.

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Clinical Trials and Cyclic AMP in Fragile X Syndrome: A Life Journey

In November 2020, a phase II clinical trial reported extremely successful results. This clinical trial of a PDE4D inhibitor from Tetra Pharmaceuticals was conducted by Dr. Elizabeth Berry-Kravis at Rush University Medical Center and funded by FRAXA Research Foundation. In this Simons Foundation lecture, Elizabeth Berry-Kravis traces 30 years of Fragile X research, from identifying its cause, through finding dozens of treatment targets, through a series of disappointing clinical trials.

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Parkinson’s Therapy May Hold Promise for Fragile X

A study funded by FRAXA in Italy has encouraging results for people with Fragile X: drugs that block adenosine receptors (A2A) reversed signs of Fragile X in a mouse model. 

“One of the most intriguing things about this study is that it points to an entire drug class (not just the one drug used) as potentially therapeutic for Fragile X. Many available compounds block A2A receptors, and we know they are safe and effective.

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Beneath the Surface of Fragile X Syndrome: Study Sheds Light on What’s Happening in Nerve Cells

This FRAXA-funded project has turned up some surprising results. At first, it might seem Kurosaki and Maquat have found yet another cellular process which is malfunctioning in Fragile X. But this finding is intimately related to previous findings of abnormal protein synthesis and misregulated transcription in Fragile X. FMRP (the protein lacking in Fragile X syndrome) is involved in chaperoning messenger RNAs within cells to active sites, and in controlling their translation into many different proteins. Some of these proteins are transcription factors, which feed back to the nucleus to control gene expression.

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Integrating Human and Mouse Studies in Fragile X Syndrome – an NIH Center Approach

Presentations by:
Craig Erickson – Translational medicine and mechanistic studies of brain neurophysiology in Fragile X Syndrome: A NIH Center Overview
Ernest Pedapati – Network Mechanisms, Biomarkers, and Pharmacology of Fragile X Syndrome in Humans
Devin Binder – Network Mechanisms of Neurophysiology and Behavior in mouse models of Fragile X Syndrome
Kimberly Huber – FMRP Regulation of local and long-range neocortical circuits in the mouse: Links with EEG phenotypes

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Scientists Find a New Way to Reverse Symptoms of Fragile X

Bear lab (Bear 3rd from left, McCamphill on right)

FRAXA Investigator and MIT Professor Mark Bear and his colleagues have identified a valuable new target for Fragile X therapeutics: GSK3 alpha. Several FRAXA research teams previously identified GSK3 beta as a treatment target for Fragile X. The catch is that, so far, GSK3 beta inhibitors have proven too toxic for regular use. Dr. Bear’s new discovery opens up the possibility of developing more selective compounds with less toxicity and fewer side effects. Interestingly, lithium inhibits both GSK3 versions – alpha and beta.

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Ketogenic Diet Eases Symptoms in Fragile X Male Mice

Fragile X Researcher, Cara Westmark, PhD

The Westmark laboratory continues to study sleep and rest-activity cycles in Fragile X mice as a potential outcome measure that correlates between preclinical and clinical research. The analysis of sleep EEG in the mice has proven more labor intensive than they anticipated, but the team is collaborating with Dr. Rama Maganti’s laboratory at UW-Madison on the development of computer scrips to speed up the analysis.

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fNIRS to Measure Treatment Response in Young Children with Fragile X

FRAXA Research Foundation has awarded a $90,000 research grant to Dr. Craig Erickson and Dr. Elizabeth Smith at Cincinnati Children’s Hospital to test functional near-infrared spectroscopy (fNIRS), in children who have Fragile X syndrome. fNIRS is safe, non-invasive, and easily-tolerated. It uses light sources and sensors on the scalp to build a heat map of the brain in action.

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Results Reported: Using EEG Responses to Sound for Fragile X Drug Discovery

Dr. Jonny Lovelace and Dr. Khaleel Razak

Jonathan Lovelace, a FRAXA funded Postdoc at UC Riverside, has made some exciting EEG findings over the past few years studying auditory hypersensitivity in mice and therapeutic drug treatments. A big obstacle in FXS research has been establishing reliable, unbiased, and translation relevant biomarkers that can be used to determine the effectiveness of therapies. One of the most important discoveries they have made is the striking similarity in EEG biomarkers between mice and humans.

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Targeting Adiponectin to Treat Fragile X Syndrome

Dr. Bettio, Dr. Christie, Dr. Thacker

FRAXA Research Foundation has awarded a $30,000 research grant to principal investigator Brian Christie, PhD, and postdoctoral fellows Jonathan Thacker, PhD, and Luis Bettio, PhD, at the University of Victoria. They are investigating whether boosting the hormone adiponectin can effectively treat Fragile X syndrome. This project is funded in partnership with the Fragile X Research Foundation of Canada, which is providing an additional $15,000.

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