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

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 • Completed Research Grant • Treatment Targets • Zukin, Suzanne February 2, 2017March 30, 2018mTOR

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 • Completed Research Grant • Disease Mechanisms • Doering, Laurie • McMaster University, Canada • Scott, Angela • Treatment Targets September 14, 2016March 30, 2018astrocytes

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 Grant • Pichon, Jacques • Treatment Targets • University of Orleans, France September 12, 2016August 6, 2018autism, BK channel, neural stem cells

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 Grant • 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 • Kurosaki, Tatsuaki • Maquat, Lynne • Treatment Targets • University of Rochester September 8, 2016April 19, 2018Boston Bruins Foundation, mRNAs

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 • Current Research Grants • Disease Mechanisms • National Institute of Mental Health • Smith, Carolyn B. • Treatment Targets September 5, 2016January 3, 2019sleep

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 Grant • 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 Grant • 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 • Completed Research Grant • Drug Repurposing • Jongens, Tom • McBride, Sean • Pepper, Anita • Treatment Targets • University of Pennsylvania September 13, 2015April 25, 2018ERK, FDA, fruit fly, glutamate, lithium, metformin, mGluR, mTOR

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.

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2014 Grants • 2015 Grants • Completed Research Grant • Disease Mechanisms • Lombroso, Paul • Research Grant with Results • Treatment Targets • Yale University February 26, 2015May 16, 2018AMPA, AMPAkines, autism, glutamate, LTD (Long-term depression), mRNAs, 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 • Cornell University • Disease Mechanisms • Jaffrey, Samie • Treatment Targets January 9, 2015January 9, 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 Grant • Drug Repurposing • Mato Santos, Susana • Ozaita, Andres • Treatment Targets • University Pompeu Fabra, Spain September 15, 2014April 25, 2018CBD, 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 • Completed Research Grant • Disease Mechanisms • Huntsman, Molly • Treatment Targets • University of Colorado September 13, 2014April 25, 2018CBD, endocannabinoid, glutamate, mGluR, 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.

Functional Interplay Between FMRP and CDK5 Signaling

FRAXA Research Foundation 2011 Grants • 2012 Grants • 2013 Grants • 2014 Grants • Biomarkers • Completed Research Grant • Disease Mechanisms • Emory University • Feng, Yue • Li, Wenqi • Treatment Targets September 13, 2014April 25, 2018Alzheimer's, CDK5, GABA, MAP1b, mGluR5, mRNAs

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.

Synaptic Characterization of Human Fragile X Neurons

FRAXA Research Foundation 2013 Grants • 2014 Grants • Disease Mechanisms • FRAXA Research Grants • Marro, Samuele • Research Grant with Results • Stanford University • Treatment Targets • Wernig, Marius September 12, 2014March 27, 2019Retinoic Acid Signaling

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.

Bcl-xL Inhibition as a Therapeutic Strategy for Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • FRAXA Research Grants • Jonas, Elizabeth • Levy, Richard • Treatment Targets • Yale University September 12, 2014April 25, 2018autism

Scientists have found increases in the numbers of neurons in brain regions of autistic children, suggesting a problem in developmental programmed cell death pathways. One of the most important effectors of neuronal survival during brain development is the “anti-cell death” protein Bcl-xL. While the normal function of Bcl-xL is to maintain a healthy number of neurons and synapses, over-expressed Bcl-xL can cause an overabundance of synaptic connections. This may be happening in Fragile X.

Seizures in Fragile X Syndrome and Therapeutic Potential of NMDA Receptor Antagonists

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • Drug Repurposing • State University of New York • Treatment Targets • Wong, Robert September 8, 2014April 28, 2018autism, glutamate, mGluR, NMDA, seizure

With a $90,000 grant from the FRAXA Research Foundation, Dr. Robert Wong is investigating how seizures are generated in Fragile X neurons. More generally, he is looking at how synapses are modified to enable learning and memory and how this process is impaired in Fragile X. $90,000 Grant Robert Wong, PhD Principal Investigator State University of New York 2013-2014 FRAXA Research Grant $90,000 over 2 Years Abnormal increases in sensitivity of a type of glutamate receptor (group I mGluR) cause brain malfunction, including epilepsy, in Fragile X syndrome (FXS). We are examining a newly uncovered regulation of this increased group I mGluR sensitivity by a second type of glutamate receptor, the NMDA receptor. By looking at audiogenic seizures in FXS model mice, NMDA receptor blockers were found to robustly suppress these seizures at the young developmental stage. In contrast, the same antagonists activated seizure activities, normally dormant, in adult FXS model mice and in a CGGRead more

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

FRAXA Research Foundation 2012 Grants • 2013 Grants • Completed Research Grant • Disney, Matthew • FRAXA Research Grants • Genetic Rescue • Treatment Targets • Yang, Wang-Yong January 24, 2014January 16, 2019FXTAS, RNAi

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.

Potassium Channel Modulators to Treat Fragile X

FRAXA Research Foundation 2012 Grants • 2013 Grants • 2014 Grants • Kaczmarek, Leonard • Research Grant with Results • Treatment Targets • Yale University January 7, 2014June 13, 2019BK channel, hypersensitivity, potassium channels, sound

With $246,000 in funding from FRAXA over 2012-2014, the Yale University team of Leonard Kaczmarek, PhD, showed that loss of FMRP leads to an increased Kv3.1 potassium currents and decreased Slack potassium currents in neurons. Both of these changes impair timing of action potentials in auditory neurons (and likely others throughout the brain). The team also found that the firing pattern of 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 and test advanced compounds which may reverse these deficits.

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

FRAXA Research Foundation 2012 Grants • 2013 Grants • Clinical • Completed Research Grant • Drug Repurposing • Erasmus University Rotterdam • FRAXA Research Grants • Treatment Targets • Willemsen, Rob September 13, 2013April 25, 2018AFQ056, AMPA, AMPAkines, autism, baclofen, ERK, mGluR5, minocycline, NMDA, Novartis

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.

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

FRAXA Research Foundation 2012 Grants • 2013 Grants • Completed Research Grant • Deng, Pan-Yue • Disease Mechanisms • Klyachko, Vitaly • Rotman, Ziv • Treatment Targets • Washington University September 12, 2013August 6, 2018

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.

Glycogen Synthase Kinase-3 and Fragile X

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • Completed Research Grant • Jope, Richard • King, Margaret • Research Grant with Results • Treatment Targets • University of Miami • Yuskaitis, Christopher September 12, 2013May 9, 2019autism, GSK3, lithium, mGluR5

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.

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

FRAXA Research Foundation 2013 Grants • Biomarkers • Clinical • Completed Research Grant • Erickson, Craig • FRAXA Research Grants • Schaefer, Tori • Treatment Targets September 9, 2013April 25, 2018GABA, GABA-A

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.

Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

FRAXA Research Foundation 2012 Grants • 2013 Grants • Broadie, Kendal • Completed Research Grant • Disease Mechanisms • Drug Repurposing • Gatto, Cheryl • Treatment Targets • Vanderbilt University September 2, 2013April 25, 2018fruit fly, matrix metalloproteinase, minocycline, RNAi

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.