Treatment Targets Archives • Page 2 of 5 • Fragile X Research

MicroRNA Mediated Astroglial GLT1 Dysregulation in Fragile X

FRAXA Research Foundation 2017 Grants • 2018 Grants • Completed Research Grants • Disease Mechanisms • Higashimori, Haruki • Men, Yuqin • Treatment Targets • Tufts University • Yang, Yongjie September 30, 2017October 13, 2020astrocytes, autism, glutamate, Pierce Family Fragile X Foundation

Almost all brain research focuses on neurons – nerve cells. However, the brain has many more glial cells which support, nourish, and protect the neurons. FRAXA Research Foundation awarded a 2017 grant $90,000 to support Dr. Yang’s studies of how changes in glial cells contribute to Fragile X syndrome. This grant is funded by a grant from the Pierce Family Fragile X Foundation.

Autophagy is a Novel Therapeutic Target of Impaired Cognition in Fragile X Syndrome

FRAXA Research Foundation 2017 Grants • 2018 Grants • Albert Einstein College of Medicine • Disease Mechanisms • Research Grant Results • Treatment Targets • Zukin, Suzanne September 27, 2017October 10, 2019mTOR, NIH, PSD-95

Dr. Suzanne Zukin, at Albert Einstein College of Medicine, is expert on signaling pathways in the brain and the regulation of synaptic plasticity. With this 2017 grant of $90,000 from FRAXA Research Foundation, she and her team are exploring autophagy, which is how cells clean house, in Fragile X.

Defining Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • Biomarkers • FRAXA Research Grants • Hogan, Carolyn Ann • Kumar, Vikas • O'Malley, Karen • Research Grant Results • Treatment Targets • Washington University September 22, 2017March 27, 2019glutamate, mGluR5, NIH

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).

Mechanisms of Tolerance to Chronic mGluR5 Inhibition

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Bear, Mark • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Osterweil, Emily • Research Grant Results • Senter, Rebecca • Treatment Targets September 19, 2017May 21, 2021AFQ056, drug tolerance, glutamate, lovastatin, mGluR5, NIH, Novartis, Roche

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.

Prefrontal Cortex Network (PFC) Dynamics in Fragile X Syndrome

FRAXA Research Foundation 2016 Grants • 2017 Grants • Disease Mechanisms • Johnston, Daniel • Research Grant Results • Siegel, Jennifer • Treatment Targets • University of Texas at Austin September 18, 2017October 10, 2019NIH

With a $90,000 grant from FRAXA Research Foundation from 2016-2017, Dr. Daniel Johnston and Dr. Jenni Siegel at the University of Texas at Austin are analyzing pre-frontal cortex (PFC) dysfunction in the Fragile X model. They have preliminary evidence that Fragile X mice are severely impaired in a prefrontal cortex (PFC)-dependent task.

Altered Neural Excitability and Chronic Anxiety in a Mouse Model of Fragile X

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • 2016 Grants • Completed Research Grants • Disease Mechanisms • Scripps Research Institute • Treatment Targets • Vanderklish, Peter September 13, 2017January 16, 2019AMPK, GSK3

With a $35,000 grant from FRAXA Research Foundation in 2016, Dr. Peter Vanderklish at Scripps Research Institute, and colleagues, explored the basis of anxiety in Fragile X syndrome.

Development of a High-Content Synapse Assay to Screen Therapeutics for Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Bear, Mark • Bhakar, Asha • Completed Research Grants • Drug Repurposing • FRAXA Research Grants • Massachusetts Institute of Technology (MIT) • Treatment Targets September 8, 2017March 30, 2018autism, FDA, mGluR5, NIH

With a $45,000 grant from FRAXA Research Foundation in 2009, Dr. Mark Bear and Dr. Asha Bhakar used High Content Screening (HCS) to develop an assay sensitive to the effect of the FXS genotype. This project was funded in full by NIH after the first year.

Clinical Trial of Ganaxolone in Patients with Fragile X Syndrome

FRAXA Research Foundation 2014 Grants • 2015 Grants • Clinical • Dijck, Anke Van • Has Results • Kooy, Frank • Research Grant Results • Treatment Targets • Trials and Studies • University of Antwerp, Belgium September 2, 2017March 9, 2020drug tolerance, GABA, GABA-A, ganaxolone, glutamate, mGluR, seizure, sleep

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.)

Preclinical Testing of Sleep-Wake Patterns as an Outcome Measure for Fragile X

Theodore Coutilish 2016 Grants • 2017 Grants • 2018 Grants • Biomarkers • Completed Research Grants • Treatment Targets • University of Wisconsin • Westmark, Cara May 23, 2017February 14, 2022Alzheimer's, drug repurposing, EEG, seizure, sleep, sound

FRAXA Research Foundation awarded $122,000 over 2016-2018 to Dr. Cara Westmark at the University of Wisconsin at Madison for studies of sleep disorders in Fragile X syndrome.

Which is the right FMRP for Therapeutic Development of Fragile X Syndrome?

FRAXA Research Foundation 2016 Grants • Completed Research Grants • Cornell University • Disease Mechanisms • Gan, Wen-Biao • Jaffrey, Samie • Treatment Targets April 24, 2017March 26, 2019

With a 2-year, $90,000 grant from FRAXA Research Foundation over 2016-17, Dr. Samie Jaffrey at Weill Medical College of Cornell University explored which FMRP isoform is the best target to treat Fragile X syndrome.

Fragile X Research Tackles High Anxiety – Peter Vanderklish

Theodore Coutilish Disease Mechanisms • Research Updates • Scripps Research Institute • Treatment Targets • Vanderklish, Peter February 9, 2017July 26, 2018hypersensitivity

Yes, we all know the signs of Fragile X anxiety: Ears begin turning red followed by incessant pacing, heavy breathing, stiffening body, flapping, jumping, avoidance or yelling. Sometimes, it’s the more severe screaming, pinching, scratching, biting and general tearing things up or, worse, the nuclear meltdown.

PIKE as a Central Regulator of Synaptic Dysfunction in Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • Albert Einstein College of Medicine • Research Grant Results • Treatment Targets • Zukin, Suzanne February 2, 2017October 10, 2019mGluR, mTOR, NIH

With $255,000 from FRAXA Research Foundation, Dr. Suzanne Zukin at Albert Einstein College of Medicine studied signalling pathways in Fragile X syndrome.

Correcting Defects in Astrocyte Signaling in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Doering, Laurie • McMaster University, Canada • Research Grant Results • Scott, Angela • Treatment Targets September 14, 2016February 25, 2020astrocytes, NIH

With a $90,000 grant from the FRAXA Research Foundation from 2015-2016, Dr. Laurie Doering and Dr. Angela Scott at McMasters University studied astrocytes in Fragile X. Astrocytes, brain cells which support neurons, do not transmit signals. Several treatment strategies for Fragile X have been proposed based on correction of “astrocyte phenotypes”.

Sensory Hypersensibility in Fragile X Syndrome and BK Channel Openers

FRAXA Research Foundation 2012 Grants • 2013 Grants • 2015 Grants • 2016 Grants • Briault, Sylvain • Completed Research Grants • Pichon, Jacques • Treatment Targets • University of Orleans, France September 12, 2016August 6, 2018autism, BK channel, neural stem cells, NIH

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.

MicroRNAs as Biomarkers in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Biomarkers • Completed Research Grants • FRAXA Research Grants • John Hopkins University • Meffert, Mollie • Treatment Targets September 10, 2016March 30, 2018

With a $90,000 grant from FRAXA Research Foundation in 2015-2016, Dr. Mollie Meffert and Dr. Christina Timmerman at Johns Hopkins University studied groups of small RNAs, known as microRNAs, which are greatly decreased in brain tissue of Fragile X mice vs. normal controls.

Repurposing Drugs to Dampen Hyperactive Nonsense-Mediated Decay in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Drug Repurposing • Kurosaki, Tatsuaki • Maquat, Lynne • Research Grant Results • Treatment Targets • University of Rochester September 8, 2016February 11, 2021Boston Bruins Foundation, mRNAs, NIH, Roche

With a $90,000 grant from the FRAXA Research Foundation, Dr. Lynne Maquat and Dr. Tatsuaki Kurosaki will investigate nonsense-mediated mRNA decay (NMD) in Fragile X. NMD is a “housekeeping” process that cells use to prevent faulty proteins from being made. But there is too much of it in Fragile X syndrome. There are already available drugs that suppress NMD – including caffeine.

Altered Sleep in Fragile X Syndrome: Basis for a Potential Therapeutic Target

FRAXA Research Foundation 2016 Grants • 2017 Grants • 2018 Grants • Biomarkers • Completed Research Grants • Disease Mechanisms • National Institute of Mental Health • Smith, Carolyn B. • Treatment Targets September 5, 2016May 14, 2020NIH, sleep

With a $90,000 grant from FRAXA Research Foundation over 2016-2018, Dr. Carolyn B. Smith and Dr. Rache Sare at the National Institute of Mental Health investigated the basis of sleep problems in Fragile X syndrome.

Enhancement of NMDA Receptor Signaling for the Treatment of Fragile X Syndrome

Theodore Coutilish 2016 Grants • 2017 Grants • 2018 Grants • Barnes, Stephanie • Completed Research Grants • Osterweil, Emily • Research Updates • Treatment Targets • University of Edinburgh, Scotland August 15, 2016March 26, 2019ERK, glutamate, lovastatin, mGluR, NMDA, seizure

FRAXA Research Foundation funded a 2016-2017 Fellowship for Dr. Stephanie Barnes in the University of Edinburgh lab of Dr. Emily Osterweil. With this $90,000 award, the team is investigating NMDA signaling in fragile X syndrome mice.

Targeting AMP-Activated Protein Kinase Pathway in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • Biomarkers • Completed Research Grants • Scripps Research Institute • Treatment Targets • Vanderklish, Peter September 13, 2015April 25, 2018AMPK, FDA, GSK3, metformin, mGluR, mTOR, PDE4

With a $100,000 grant from the FRAXA Research Foundation in 2015, Dr. Peter Vanderklish explored a novel strategy to treat Fragile X syndrome: AMPK activators. The good news is that there are FDA approved (for example, metformin) and naturally occurring AMPK activators (such as resveratrol, found in red wine).

Fruit Flies to Model and Test Fragile X Treatments

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • 2012 Grants • 2013 Grants • 2014 Grants • 2015 Grants • Choi, Catherine • Drug Repurposing • Jongens, Tom • McBride, Sean • Pepper, Anita • Research Grant Results • Treatment Targets • University of Pennsylvania September 13, 2015May 18, 2020ERK, FDA, fruit fly, glutamate, lithium, metformin, mGluR, mTOR, NIH

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.

FRAXA Grant to Nahum Sonenberg, PhD — Effects of metformin in Fmr1 knockout mouse model of Fragile X syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Drug Repurposing • McGill University • Research Grant Results • Sonenberg, Nahum • Treatment Targets April 8, 2015May 15, 2020AMPK, FDA, metformin, mRNAs, mTOR

Mis-regulation of activity-dependent protein synthesis is one of the major cellular abnormalities found in Fragile X. Upstream neuronal signaling regulates a large cluster of enzymes called the mTORC1 complex, which in turn regulates protein synthesis. This complex is also controlled by cellular energy levels via the metabolic sensor AMP-activated Protein Kinase (AMPK). AMPK is a highly conserved kinase that is activated under conditions of energy stress, when intracellular ATP levels decline and intracellular AMP increases.

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2014 Grants • 2015 Grants • Disease Mechanisms • Lombroso, Paul • Research Grant Results • Treatment Targets • Yale University February 26, 2015May 17, 2020AMPA, AMPAkines, autism, glutamate, LTD (Long-term depression), mRNAs, NIH, seizure, STEP (STriatal-Enriched protein tyrosine Phosphatase)

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.

Molecular Mechanisms of Cytoskeletal Regulation by FMRP

FRAXA Research Foundation 2015 Grants • Completed Research Grants • Cornell University • Disease Mechanisms • Jaffrey, Samie • Treatment Targets January 9, 2015December 4, 2019mRNAs

With a 2-year, $120,000 grant from FRAXA Research Foundation in 2015, Dr. Samie Jaffrey from Weill Medical College of Cornell University will research the connection between FMR1, RhoA, and dendritic spine abnormalities.

Targeting the Endocannabinoid System in Adult Fragile X Mice

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grants • Drug Repurposing • Mato Santos, Susana • Ozaita, Andres • Treatment Targets • University Pompeu Fabra September 15, 2014May 17, 2020CBD, endocannabinoid, rimonabant

With a $90,000 grant from the FRAXA Research Foundation from 2013-2014, Dr. Andres Ozaita led a team to test rimonabant’s ability to blockade the CB1 receptor. Blocking CB1 has shown potential to reverse most symptoms of disease in mice bred to mimic Fragile X syndrome.

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

FRAXA Research Foundation 2013 Grants • 2014 Grants • Cea-Del Rio, Christian • Disease Mechanisms • Huntsman, Molly • Research Grant Results • Treatment Targets • University of Colorado September 13, 2014May 25, 2020CBD, endocannabinoid, glutamate, mGluR, NIH, seizure, somatostatin

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 in 2013-2014, Dr. Molly Huntsman’s team examined how these networks interact and how inhibitory deficits can best be remedied.