Novel Modulators of Potassium Channels to Treat Fragile X

Novel Modulators of Potassium Channels to Treat Fragile X

With funding from FRAXA, the Yale University team of Leonard Kaczmarek, PhD showed that the firing pattern of suditory neurons in response to repeated stimulation is severely abnormal in Fragile X mice. Based on these results, they are collaborating with the UK-based company Autifony to develop advanced compounds which may reverse these deficits.

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Fragile X Syndrome Drug Validation Initiative (FRAXA-DVI)

Fragile X Syndrome Drug Validation Initiative (FRAXA-DVI)

The FRAXA Drug Validation Initiative (FRAXA-DVI) provides speedy, cost-effective, objective preclinical testing of potential new Fragile X treatments. FRAXA has funded FRAXA-DVI for $50,000 or more per year since 2012.

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Defining the Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

Defining the Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

With $217,500 in grants from FRAXA Research Foundation, Dr. Karen O’Malley and team studied the function of mGluR5 when it is inside cells. Many of the symptoms of Fragile X Syndrome (FXS) are thought to arise due to overactive metabotropic glutamate receptor 5 (mGluR5) signaling, which is normally opposed by the protein missing in FXS, Fragile X Protein (FMRP).

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Biomarker Discovery and Validation for Fragile X Syndrome

Biomarker Discovery and Validation for Fragile X Syndrome

With a $60,000 grant from FRAXA Research Foundation in 2015 that was renewed in 2016, Dr. Eric Klann of New York University will research biomarkers in fraile X syndrome and how to translate these markers from mouse models to human patients.

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Sensory Hypersensibility in Fragile X Syndrome and BK Channel Openers

Sensory Hypersensibility in Fragile X Syndrome and BK Channel Openers

With $366,100 in grants from FRAXA Research Foundation, these investigators at the University of Orleans studied sensory abnormalities in Fragile X mice and test the ability of a class of drugs, BK channel openers, to rescue these abnormalities.

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Fragile X Mutant Mouse Facility

Fragile X Mutant Mouse Facility

With $375,000 in grants from the FRAXA Research Foundation since 2009, Dr. David Nelson has developed an impressive array of advanced mouse models of Fragile X, at Baylor College of Medicine. These models are available to investigators worldwide on request. This resource has been essential for a broad, rapid distribution of Fragile X and related gene mouse models and has increased the pace of Fragile X research.

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Fruit Flies to Model and Test Fragile X Treatments

Fruit Flies to Model and Test Fragile X Treatments

Dr. Jongens and his collaborators have found an insulin-like protein in the fly brain that is overexpressed in the Fragile X mutant fly, leading to increased activity of the insulin signaling pathway. Furthermore, they found that certain behavioral patterns in the Fragile X flies can be rescued by expressing the FX gene just in insulin producing neurons in the fly brain. In the mutant, there are other changes in the signaling pathways, including a decrease in cAMP and elevation in PI3K, mTOR, Akt and ERK activity. They now propose to study 2 medicines used for diabetes: pioglitazone (increases cAMP and decreases Akt and ERK) and metformin (inhibits mTOR), in flies and mice to validate the potential efficacy of these novel therapeutics for Fragile X.

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Studies of Mega Green Tea Extract to Treat Fragile X Syndrome

Studies of Mega Green Tea Extract to Treat Fragile X Syndrome

With a $124,000 grant from the FRAXA Research Foundation from 2012-2014, Dr. Mara Dierssen and Dr. Rafael de la Torre conducted preclinical studies in Fragile X knockout mice and a clinical trial in Fragile X patients using Mega Green Tea Extract, which contains 45% by weight epigallocatechin gallate (EGCG).

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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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Small Molecules To Target r(CGG) Expansions to Treat Fragile X Syndrome

Small Molecules To Target r(CGG) Expansions to Treat Fragile X Syndrome

With a 2-year, $90,000 grant from FRAXA Research Foundation, Dr.’s Matthew Disney and Wang-Yong Yang worked to correct the underlying problem in Fragile X: the silencing of the Fragile X gene (FMR1) and the resulting lack of FMRP (Fragile X Mental Retardation Protein). Their approach was to use novel small molecules to target the abnormal CGG repeats before the FMR1 gene.

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Social Behavior as an Outcome Measure for Fragile X Clinical Trials

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

One of the features of the Fragile X mouse model which is relevant to the human Fragile X syndrome (and autism) is social behavior. Several tests show consistent social behavioral abnormalities in the Fragile X mouse model. With a $140,000 grant from FRAXA Research Foundation in 2012-2013, Dr. Willemsen at Erasmus University used social behavior tests to measure the effectiveness of several drug strategies.

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Translation-Independent Functions of FMRP in Excitability, Synaptic Transmission and Plasticity

Translation-Independent Functions of FMRP in Excitability, Synaptic Transmission and Plasticity

With a $140,000 grant from FRAXA Research Foundation, Dr. Vitaly Klyachko and team at Washington University explored STP (short-term plasticity) in Fragile X, namely looking at presynaptic calcium dynamics as a major underlying cause of the STP defects.

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Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

With a $157,000 grant from the FRAXA Research Foundation in 201202013, Dr. Kendal Broadie and Dr. Cheryl Gatto worked to define the distinct but also overlapping roles for MMP-1 and MMP-2 in synaptic structural and functional development. In drug studies with Fragile X fruit flies, they will be testing a range of MMPIs in drug treatments to compare effectiveness during development and at maturity, in order to define the contributions of FXS developmental impairments and adult recovery/plasticity.

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Endocannabinoid Mediated Synaptic Plasticity in Fragile X Mice

Endocannabinoid Mediated Synaptic Plasticity in Fragile X Mice

With a $90,000 grant from FRAXA Research Foundation over two years, Drs. Olivier Manzoni and Daniela Neuhofer researched the relationship between Fragile X syndrome and the areas of the brain that are involved in reward processing, regulation of emotional behavior and emotional memory as well as attention, planning and working memory.

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Effects of minocycline on vocal production and auditory processing in a mouse model of Fragile X

Effects of minocycline on vocal production and auditory processing in a mouse model of Fragile X

Khaleel Razak, PhD – University of California, Riverside with Iryna Ethell, PhD Co-Principal Investigator FRAXA Awards: $45,000 in 2016 $45,000 in 2013 $45,000 in 2012 2013 Update by Khaleel Razak, PhD The goals of our FRAXA-funded research project are to determine robust biomarkers relevant to the FXS and to examine the efficacy of minocycline treatment. We particularly focus on the symptoms related to communication from both production and reception viewpoints. We have identified multiple biomarkers in the Fmr1 knockout (KO) mice with the first year’s funding. There is a deficit in ultrasonic vocalizations (USV) in the KO mice. When male mice are paired with females, the KO males call at significantly slower rates (Rotschafer et al., 2012). Minocycline treatment during the first month of life, reverses the USV deficits. Based on this promising finding of a potentially useful pre-clinical outcome measure, we have pursued identification of critical developmental time windows

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Creation of a Mouse Model to Test FMR1 Gene Reactivation

Creation of a Mouse Model to Test FMR1 Gene Reactivation

With $146,000 grant from FRAXA Research Foundation over 2012-2013, Drs. Anita Bhattacharyya and Xinyu Zhao at the University of Wisconsin developed a new mouse model of Fragile X syndrome which will enable testing of gene reactivation and gene therapy approaches to treatment. They transplanted human Fragile X neural cells differentiated from induced pluripotent stem cells into brains of neonatal mice and then testing for FMR1 reactivation. In 2015, The John Merck Fund assumed support for this work with a generous grant of $750,000 to the scientists.

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Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome

Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome

With a $474,300 grant from FRAXA Research Foundation from 2000-2013, Dr. Kimberly Huber and her team at the University of Texas conducted several studies on the relationship between mGluR5 and Fragile X syndrome. Dr. Huber made the original discovery of the mGluR Theory of Fragile X when she was a postdoctoral fellow in the lab of Dr. Mark Bear, with her first FRAXA grant in 2000.

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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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Small Rho GTPases, a Potential Therapeutic Target for Fragile X Syndrome

Small Rho GTPases, a Potential Therapeutic Target for Fragile X Syndrome

With $384,345 in grants from FRAXA Research Foundation, Dr. MariVi Tejada from the University of Houston focused on a particularly promising point of intervention in pathways of brain receptors, and tested several potential therapeutic compounds in an attempt to rescue function in the mouse model of Fragile X.

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Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome

Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome

Dr. Huber made the original discovery of the mGluR Theory of Fragile X when she was a postdoctoral fellow in the lab of Dr. Mark Bear, with her first FRAXA grant in 2000. Dr. Huber has received $474,300 in grants from FRAXA Research Foundation since then, researching molecular mechanisms and developmental switches in Fragile X syndrome. She has worked with 4 FRAXA Postdoctoral Fellows (Elena Nosyreva, PhD in 2006; Jennifer Roseni, PhD in 2007; Tong Zang, PhD in 2010-2011; and Weirui Guo, PhD in 2012-2013) and has received supporting funds from The Meadows Foundation of/for Texas.

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Ab-Mediated Translation in Fragile X Syndrome

Ab-Mediated Translation in Fragile X Syndrome

With a $120,000 grant from FRAXA Research Foundation during 2011-2012, Dr. Cara Westmark at the University of Wisconsin explored the role of AbPP as a potential treatment option for fragile X. AbPP produces b-amyloid which is over-expressed in Alzheimer’s disease (AD) and Down syndrome. 

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Glycogen Synthase Kinase-3 and Fragile X

Glycogen Synthase Kinase-3 and Fragile X

With $208,000 in funds from FRAXA Research Foundation, Dr. Richard Jope and his team at the University of Miami tested whether newly developed, highly specific inhibitors of GSK3 can reduce behavioral abnormalities in Fragile X mice.

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Synaptic Actin Signaling Pathways in Fragile X

Synaptic Actin Signaling Pathways in Fragile X

With a $163,356 grant from FRAXA Research Foundation in 2010-12, Dr. Scott Soderling and Dr. Hwan Kim at Duke University bred the standard mouse model of Fragile X syndrome to their lines of mice that express reduced levels of several key proteins that modulate synaptic actin. These compound mutant mice were compared to FXS mice to determine if genetically impairing pathways to the actin cytoskeleton can rescue deficits in the FXS mice.

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Genetic and Pharmacologic Manipulation of PI3K Activity in FXS: Assessing Potential Therapeutic Value

Genetic and Pharmacologic Manipulation of PI3K Activity in FXS: Assessing Potential Therapeutic Value

With a $90,000 grant from the FRAXA Research Foundation, Dr. Gary Bassell and his team at Emory University explored the PI3K/mTOR signaling complex in FXS via genetic and pharmacologic rescue approaches, to reduce the enzymatic function of specific components of this complex pathway in an FXS mouse model.

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