Retinoic Acid Signaling Blocked by Fragile X Mutation

Retinoic Acid Signaling Blocked by Fragile X Mutation

A 2013-2014 FRAXA Research Grant, Synaptic Characterization of Human Fragile X Neurons, has shown that the Fragile X mutation impairs homeostatic plasticity in human neurons, by blocking synaptic retinoic acid signaling.

Principal Investigator Marius Wernig, PhD and FRAXA Postdoctoral Fellow Samuele Marro, PhD at Stanford University used stem cells from human adults, instead of mouse cells, for this study. They found promising results with retinoic acid which is a metabolite of Vitamin A. The system they have developed could provide a powerful new cellular biomarker for screening many treatment approaches.

Dr. Marro provided us with the following summary of the published results.

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Aripiprazole as a Treatment for Fragile X Syndrome

Aripiprazole as a Treatment for Fragile X Syndrome

Many medications are used to help people with Fragile X cope. But few clinical trials have been done on these drugs. Years ago FRAXA funded Dr. Craig Erickson to run a trial of aripiprazole (aka Abilify). FRAXA guest writer Hannah Miles recently caught up with Dr. Erickson to learn the results of the trial.

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Lovamix: Clinical Trial of Combined Treatment of Minocycline and Lovastatin in Fragile X Syndrome

With a $66,714 grant from the FRAXA Research Foundation awarded over 2015-2017, Dr. Francois Corbin at the Universite of Sherbrooke will test the safety and synergistic effects of lovastatin and minocycline in patients with Fragile X syndrome.

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Mechanisms of Tolerance to Chronic mGluR5 Inhibition

Mechanisms of Tolerance to Chronic mGluR5 Inhibition

Over the past few years, both Novartis and Roche sponsored large-scale clinical trials of metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) to treat Fragile X syndrome (FXS). With a $90,000 grant from FRAXA Research Foundation in 2015-2017, Dr. Mark Bear’s team will explore if mGlu5 NAMs dosed chronically causes tolerance, and if so, how it develops and to probe new avenues to prevent or circumvent it.

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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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Analysis of Developmental Brain Dysfunction in Families

Analysis of Developmental Brain Dysfunction in Families

FRAXA Research Foundation is proud to make a grant of $90,000 over 2014-2015 to Margaret King, PhD. The goal of this project is to identify new approaches to clinical trial design for Fragile X pharmaceuticals.

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Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

With a $349,000 grant from FRAXA Research Foundation from 2008-2015, Dr. Paul Lombroso and his team at Yale University researched if inhibiting STEP could reduce behavioral abnormalities in Fragile X syndrome. Results published.

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Synaptic Characterization of Human Fragile X Neurons

Synaptic Characterization of Human Fragile X Neurons

With a $90,000 grant from FRAXA Research Foundation over 2013-14, Dr. Marius Wernig and Dr. Samuele Marro at Stanford analyzed homeostatic plasticity and regulation of synaptic strength by retinoic acid. If the results are encouraging, they will move forward with testing whether available RA antagonists can alleviate observed abnormalities in these cells.

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Altered Cyclic AMP Signaling in Fragile X

Altered Cyclic AMP Signaling in Fragile X

With $125,000 grant from FRAXA Research Foundation over 2006-2008, Dr. Anita Bhattacharyya at the University of Wisconsin Waisman Center investigated abnormalities in cyclic AMP signaling in Fragile X syndrome. Results published.

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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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Hypothalamic Pituitary Adrenal (HPA) Axis Dysregulation in Fragile X Syndrome

Hypothalamic Pituitary Adrenal (HPA) Axis Dysregulation in Fragile X Syndrome

The hypothalamic pituitary adrenal (HPA) axis is our central stress response system. FRAXA Research Foundation awarded Dr. Carolyn B. Smith $62,000 in funding in 2005 to explore the HPA axis in Fragile X mice. The results of their study indicate that, in FVB/NJ mice, the hormonal response to and recovery from acute stress is unaltered by the lack of Fragile X mental retardation protein. Results published.

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Role of Experience in Regulating Levels of the Fragile X Protein

Role of Experience in Regulating Levels of the Fragile X Protein

FRAXA Research Grant to Kenneth J. Mack, MD, PhD — Mayo Clinic with Peter K. Todd, MD, PhD, Postdoctoral Fellow   FRAXA Awards: $29,000 in 2001 $20,000 in 2000 Final Report on Dr. Mack’s Project While a professor at University of Wisconsin-Madison, Dr. Mack investigated whether and how FMRP levels are regulated in response to neuronal stimulation in vivo (in live animals). He looked at the effects of seizures and of experience in his experiments. Dr. Mack and colleagues published their findings in the Proceedings of the National Academy of Sciences: The Fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95 Peter K. Todd, Kenneth J. Mack, and James S. Malter PNAS | November 25, 2003 | vol. 100 | no. 24

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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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