Pharmacological Tolerance in the Treatment of Fragile X Syndrome

Pharmacological Tolerance in the Treatment of Fragile X Syndrome

With a $90,000 grant from FRAXA Research Foundation, Dr. Patrick McCamphill and Dr. Mark Bear at Massachusetts Institute of Technology (MIT) will further investigate drug tolerance and ways to overcome it. 

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Fragile X Clinical Trial of AZD7325 in Adults

Fragile X Clinical Trial of AZD7325 in Adults

With a $51,000 grant from FRAXA Research Foundation, Dr. Craig Erickson will conduct a double-blind, placebo-controlled clinical trial of AZD7325 in adults with Fragile X syndrome at Cincinnati Children’s Hospital.  The compound being studied is an investigational new drug from AstraZeneca that targets GABA (A) receptors.

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In Their Own Words: Reports From the International Fragile X Workshop

In Their Own Words: Reports From the International Fragile X Workshop

The 18th International Fragile X and Related Neurodevelopmental Disorders Workshop in Quebec, Canada, was a great success, featuring Fragile X much more heavily than any previous meeting in this series! We asked our speakers to summarize their work in their own words. These brief updates from researchers investigating Fragile X.

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Brain Imbalance Target of Dr. Erickson’s New Clinical Trial

Brain Imbalance Target of Dr. Erickson’s New Clinical Trial

According to Dr. Erickson, AZD7325 is a drug that selectively boosts GABA neurotransmission in the brain. GABA is the primary neurochemical in the brain that blocks brain activation. GABA activity is in balance in the brain with Glutamate activity, which is the primary neurochemical that causes brain activation. In Fragile X, GABA activity is insufficient and glutamate activity is excessive, likely causing brain activity to be out of balance. AZD7325 attempts to correct parts of this imbalance by boosting the insufficient GABA activity in the brains of people with Fragile X

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Can NKCC1 Inhibitors Correct Synaptic and Circuit Hyperexcitability in Fragile X Syndrome?

Can NKCC1 Inhibitors Correct Synaptic and Circuit Hyperexcitability in Fragile X Syndrome?

With $258,000 in grants since 2013 from FRAXA Research Foundation, Dr. Anis Contractor and Dr. Qionger He at Northwestern University are exploring the potential of the available drug bumetanide to correct altered GABA signalling in a mouse model of Fragile X syndrome.

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Clinical Trial of Ganaxolone in Patients with Fragile X Syndrome

Clinical Trial of Ganaxolone in Patients with Fragile X Syndrome

With a $90,000 grant from FRAXA Research Foundation funded during 2014-2015, Dr. Frank Kooy and colleagues at the University of Antwerp are conducting a double blind crossover trial of ganaxolone in patients with Fragile X syndrome. Results of this study were mixed (see Marinus: Results from Phase 2 Exploratory Clinical Study Support Continued Development of Ganaxolone in Fragile X Syndrome.

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A Kinase Assay as a Biomarker for Fragile X Syndrome

A Kinase Assay as a Biomarker for Fragile X Syndrome
With a $90,000 grant from FRAXA Research Foundation over 2017-2018, Dr. Frank Kooy at the University of Antwerp, Belgium, is investigating whether phosphorylation abnormalities are a suitable biomarker for the Fragile X syndrome. $90,000 Grant Drs. Anke Van Dijck (FRAXA fellow, ganaxolone clinical trial), Ilse van der Werf, Geert Vandeweyer, Elisa Cappuyns (FRAXA fellow, this study), Frank Kooy R. Frank Kooy, PhD Principal Investigator University of Antwerp 2018 FRAXA Research Grant $90,000 over 2 Years “This Is Your Brain on Drugs” was a large-scale US anti-drugs TV campaign promoted by Partnership for a Drug-Free America in 1987. The purpose was to discourage use of illegal drugs by showing an egg frying in a pan simulating what drugs can due to your brain. It was incredibly simple and effective. TV Guide named it one of the top 100 commercials of all time. University of Antwerp researcher Frank Kooy, PhD, has a completely different updateRead more

GABA-A Receptor in Fragile X Syndrome

GABA-A Receptor in Fragile X Syndrome
FRAXA Research Foundation funded studies under the direction of Dr. Frank Kooy at the University of Antwerp in Belgium. $210,000 GrantsFrank Kooy, PhD Principal Investigator University of Antwerp, Belgium FRAXA Research Grants $45,000 in 2010 $100,000 in 2007-8 $65,000 in 1999-2000 by Frank Kooy, PhD Absence of a single protein, FMRP, in Fragile X patients leads to a cascade of molecular events in brain cells. To find out which other genes are involved the clinical symptoms, we have been looking for genes that are differentially expressed in Fragile X syndrome. One of the genes specifically underexpressed is part of the GABAA receptor. As GABA-A receptors are the main inhibitory receptors in the brain, involved in processes like anxiety, mood swings, sleep and cognition, processes also disturbed in Fragile X patients, we followed up on this finding. In subsequent studies, we demonstrated abnormalities in expression levels of multiple parts of the GABA-ARead more

Functional Interplay Between FMRP and CDK5 Signaling

Functional Interplay Between FMRP and CDK5 Signaling

With a $180,000 grant from the FRAXA Research Foundation over 2011-2014, Dr. Yue Feng and Dr. Wenqi Li at Emory University will study CDK5 pathway function and regulation in an effort to break down whether and how CDK5 signaling is affected by the loss of the Fragile X protein, FMRP, in the Fragile X mouse model.

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Functional Interplay Between FMRP and CDK5 Signaling

Functional Interplay Between FMRP and CDK5 Signaling

Yue Feng, PhD — Emory University School of Medicine with Wenqi Li, PhD, Postdoctoral Fellow FRAXA Awards:  $180,000 $45,000 in 2013 renewed for $45,000 in 2014 $45,000 in 2011 renewed for $45,000 in 2012     Weakened synaptic development and synaptic plasticity, as a result of lacking the functional Fragile X protein (FMRP), underlies the intellectual disability in Fragile X Syndrome (FXS). Decades of  investigation established the role of FMRP in binding its mRNA targets and regulating translation in response to neuronal and synaptic activity changes. Exciting discoveries on two receptors, mGluR5 and GABA, signaling in FXS animal models have led to promising therapeutic approaches based on variation of synaptic activity by mGluR5 antagonists and GABA agonists. However, clinical trials only achieved partial reverse of FXS phenotype. Thus, developing additional therapeutic strategies for treating the full spectrum of FXS symptoms are still pressing challenges. The identification of genome-wide  Fragile X protein (FMRP)  target mRNAs by recent discoveries provides important clues

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Development of a Novel GABA-A Agonist in Fragile X Syndrome

Development of a Novel GABA-A Agonist in Fragile X Syndrome

Of the many genes known to be regulated by FMRP, the gamma-aminobutyric acid receptor A (GABA(A)), is gaining attention as a potential target for the treatment of FXS. Mounting evidence suggests decreased expression and functioning of GABA(A) is involved in the pathophysiology of FXS. Non-selective GABA(A) agonism in animal models of FXS has been associated with normalization of morphological features, GABA(A) expression, and behavior. However, the clinical use of these agents in Fragile X is associated with unwanted side-effects, such as sedation, dulling of cognition, and occasional paradoxical agitation, which limits their use. Given the limitations in available GABA(A)-based treatment of FXS, this group plans to investigate a novel selective GABA(A) agonist in a mouse model of FXS. This agent has the potential to relieve many symptoms of Fragile X without the unwanted side effects.

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Tori Schaefer, PhD — Cincinnati Children’s Hospital

Tori Schaefer, PhD — Cincinnati Children’s Hospital

Development of a Novel GABA(A) a2,3 Agonist in Fragile X Syndrome with Craig Erickson, MD, Consultant FRAXA Awards: $21,000 in 2013 SUMMARY: Dr. Schaeffer used this 2013 grant from FRAXA Research Foundation to analyze an investigational new compound that targets the GABA-A receptor. This study has led to a clinical trial of the compound, led by Dr. Craig Erickson at Cincinnati Children’s Hospital. Of the many genes known to be regulated by FMRP, the gamma-aminobutyric acid receptor A (GABA(A)), is gaining attention as a potential target for the treatment of FXS. Mounting evidence suggests decreased expression and functioning of GABA(A) is involved in the pathophysiology of FXS. Non-selective GABA(A) agonism in animal models of FXS has been associated with normalization of morphological features, GABA(A) expression, and behavior. However, the clinical use of these agents in Fragile X is associated with unwanted side-effects, such as sedation, dulling of cognition, and occasional

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The Endocannabinoid System in a Mouse Model of Fragile X Syndrome

With a $128,500 grant over 2011-2013 from FRAXA Research Foundation, Drs. Bradley Alger and and Ai-Hui Tang at the University of Maryland researched endocannabinoid pathways in Fragile X.

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What Works, and What Doesn’t

At the start, it’s always hard to know what methods will work best for something as complex as the development of disease-modifying treatments for Fragile X. But, we’ve always tried to let the science lead us down the right path. At this point, the results are unequivocal, and they have shaped how we are looking for the Next Great Thing in Fragile X treatments. As a bit of background, it’s worth noting that there are two basic ways of approaching treatment research for any disease: rational drug discovery vs. high-throughput screening. Rational drug discovery means exploring the basic mechanism of disease and identifying specific “treatment targets” that might be expected to correct the underlying problem. Usually, the target is an enzyme (a protein which facilitates biochemical reactions in the cell) or a receptor (a protein, usually on the cell surface, which detects small amounts of a chemical messenger, such asRead more

A Metabolomic Drug Efficacy Index to Test Treatments in the Fragile X Mouse

A Metabolomic Drug Efficacy Index to Test Treatments in the Fragile X Mouse

Dr. Davidovic has been examining changes in metabolism in various brain regions that are affected in Fragile X patients. She has defined a brain-specific metabolic signature of FXS and is testing treatment strategies to restore normal levels of these metabolites.

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GABAergic Inhibitory Function in Fragile X Syndrome

GABAergic Inhibitory Function in Fragile X Syndrome

With a $100,000 grant from FRAXA Research Foundation, Drs. Joshua Corbin and Molly Huntsman from the Children’s National Medical Center examined the role of a particular class of brain cells (inhibitory interneurons) that dampen excessive activity in the “emotional center of the brain” (the amydala). This inhibition is deficient in Fragile X, and so they are looked for ways to remedy this. This is particularly interesting to parents of children who are overly anxious and emotional. They worked with Dr. Walter Kaufmann, a clinician at Kennedy Krieger Institute in Maryland.

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Genome-wide Epigenetic Markers in Fragile X

Genome-wide Epigenetic Markers in Fragile X

With $155,000 in grants from FRAXA Research Foundation over several years, Dr. Miklos Toth of Cornell University discovered increased startle response in Fragile X mice and that baclofen can correct this phenotype. They also studied epigenetics (ie factors other than the gene itself) which can determine symptom severity in Fragile X.

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Glutamate Metabolism in Fragile X Mouse Brain

Glutamate Metabolism in Fragile X Mouse Brain

With a $95,000 grant from FRAXA Research Foundation over 2 years, Mary McKenna at the University of Maryland studied the role of metabotropic glutamate receptors (mGluR) and how they affect other cells and pathways.

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Neurobiology of Fragile X Syndrome: A Unifying Neuro-Endocrine Hypothesis

With a $74,000 grant from FRAXA Research Foundation, Dr. Abdeslem El Idrissi at CUNY explored the GABA receptor system in Fragile X mice and tested somatostatin and taurine as potential therapies for Fragile X; while somatostatin must be infused intravenously, taurine is available as a nutritional supplement.

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The Molecular Basis of Increased Seizure Severity in the Fragile X Knockout Mouse

With a $50,000 grant from FRAXA Research Foundation from 2002-2003, Dr. Carl Dobkin and his team at the New York Institute for Basic Research studied the causes for heightened seizure activity in Fragile X mice. Results published.

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