2016 Grants Archives • Fragile X Research

FRAXA Drug Validation Initiative (FRAXA-DVI)

FRAXA Research Foundation 2011 Grants • 2012 Grants • 2013 Grants • 2014 Grants • 2015 Grants • 2016 Grants • 2017 Grants • 2018 Grants • 2019 Grants • 2020 Grants • 2021 Grants • Biomarkers • Carullo, Paulina • Cogram, Patricia • Current Research Grants • Deacon, Robert • Drug Repurposing • FLENI Foundation • Research Resources • University of Chile • University of Oxford May 6, 2021May 6, 2021BPN14770, drug repurposing, EEG, FRAXA-DVI, Healx, microbiome, Neuren Pharmaceuticals, NIH, Ovid Therapeutics, PDE4, Tetra Therapeutics, trofinetide

The FRAXA Drug Validation Initiative (FRAXA-DVI) provides speedy, cost-effective, objective preclinical testing of potential Fragile X treatments. FRAXA-DVI uses in-vitro systems, behavior batteries, and gene expression and peripheral biomarker platforms to validate investigational new drugs and repurposed available compounds in Fragile X syndrome (FXS).

Novel Modulators of Potassium Channels to Treat Fragile X

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Disease Mechanisms • Kaczmarek, Leonard • Research Grant Results • Treatment Targets • Yale University January 2, 2019October 10, 2019Autifony Therapeutics, BK channel, hypersensitivity, ion channel, potassium channels, sound

With funding from FRAXA over 2015-2017, the Yale University team of Leonard Kaczmarek, PhD showed that the firing patterns of auditory 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.

Research Points to Drugs which Inhibit PDE to Treat Fragile X

FRAXA Research Foundation 2016 Grants • 2017 Grants • 2018 Grants • Bardoni, Barbara • Current Research Grants • Disease Mechanisms • INSERM Valbonne, France • Maurin, Thomas • Treatment Targets November 4, 2018November 14, 2018mRNAs, PDE4, Tetra Therapeutics

FRAXA Research Foundation funded a grant of $90,000 over 2016-2018, for a postdoctoral fellowship for Thomas Maurin, PhD, working under the mentorship of Dr. Barbara Bardoni at INSERM in France. The team works on the biochemistry of the Fragile X protein. They have found that PDE inhibitors (a class of drugs) show promise as treatments for Fragile X syndrome. In related research, FRAXA is currently funding a clinical trial of PDE4D inhibitors.

NKCC1 Inhibitor Bumetanide Corrects Synaptic and Circuit Hyperexcitability in Fragile X Mouse Model

FRAXA Research Foundation 2013 Grants • 2014 Grants • 2016 Grants • 2017 Grants • Contractor, Anis • Drug Repurposing • He, Qionger • Northwestern University • Research Grant Results • Treatment Targets September 15, 2018February 7, 2020bumetanide, GABA, hypersensitivity, NIH, seizure

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.

Repurposing Study II: Evaluating Combinations of Drugs to Treat Fragile X

FRAXA Research Foundation 2016 Grants • 2017 Grants • 2018 Grants • Current Research Grants • Drug Repurposing • Healx February 8, 2018July 26, 2018drug combinations, drug repurposing, FDA, FRAXA-DVI, Healx

FRAXA Research Foundation initially partnered with Healx in 2016 to identify existing drugs with potential to treat Fragile X syndrome, using machine learning algorithms and computational biology. The study produced results, and now FRAXA and Healx have launched a new round of studies to evaluate combinations of compounds, including both drugs and natural products.

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

FRAXA Research Foundation 2012 Grants • 2015 Grants • 2016 Grants • 2017 Grants • Biomarkers • Clinical • Corbin, Francois • Has Results • Lepage, Jean-Francois • Research Grant Results • Trials and Studies • University of Sherbrooke, Canada October 3, 2017March 17, 2021Fragile X Meeting, lovastatin, minocycline, MRI, Roche

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.

Combinatorial Drug Treatment in a Model of Fragile X Syndrome using Novel Biomarkers

FRAXA Research Foundation 2016 Grants • 2017 Grants • Biomarkers • Lovelace, Jonny • Razak, Khaleel • Research Grant Results • Treatment Targets • University of California at Riverside October 3, 2017May 15, 2020drug combinations, EEG, hypersensitivity, matrix metalloproteinase, mGluR5, minocycline, MMP9, sound, Tetra Therapeutics

With a $90,000 grant from FRAXA Research Foundation awarded over 2016-2017, University of California researchers Khaleel Razak, PhD, and Jonathan W. Lovelace, PhD, are exploring drug combinations to limit hypersensitivity to sounds in Fragile X mice.

Targeted Transcriptional Reactivation of FMR1 in Fragile X Syndrome Stem Cells

FRAXA Research Foundation 2016 Grants • 2017 Grants • Genetic Rescue • Haenfler, Jill • Research Grant Results • Todd, Peter • University of Michigan September 23, 2017July 29, 2020CRISPR, mRNAs, NIH

With a $90,000 grant from FRAXA Research Foundation awarded in 2016, University of Michigan researcher Peter Todd, MD, PhD, is using CRISPR to selectively turn the Fragile X gene back on in stem cells.

Investigating Gene Reactivation to Treat Fragile X Syndrome

FRAXA Research Foundation 2016 Grants • 2017 Grants • 2018 Grants • Genetic Rescue • Harvard University • Lee, Jeannie • Massachusetts General Hospital • Research Grant Results September 22, 2017March 27, 2019CRISPR, Pierce Family Fragile X Foundation

With a $180,000 grant from FRAXA Research Foundation from 2016-2017, Dr. Jeannie Lee and her team at Harvard are working to reactivate the gene that is silenced in Fragile X syndrome.

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.

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, 2017May 17, 2020Alzheimer'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.

Biomarker Discovery and Validation for Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Bhattacharya, Aditi • Biomarkers • Klann, Eric • New York University • Research Grant Results March 24, 2017October 10, 2019mTOR, NIH

With a $120,000 grant from FRAXA Research Foundation over 2015-2016, Dr. Eric Klann of New York University investigated potential new biomarkers in Fragile X syndrome and how to translate these markers from mouse models to human patients.

Function of FMRP and Test of a Novel Therapeutic Approach in a Fragile X Mouse Model

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Geoffroy, Andrea • IGBMC. France • Moine, Herve • Research Grant Results September 16, 2016March 28, 2019DgkK, mRNAs

With a 2015-2016 $90,000 grant from FRAXA Research Foundation, Dr. Herve Moine and Dr. Andrea Geoffroy aim to uncover the exact role of FMRP and to test a novel possible means to correct for FMRP absence in the mouse model of 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.

Fragile X Mutant Mouse Facility

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • 2014 Grants • 2015 Grants • 2016 Grants • Baylor College of Medicine • Disease Mechanisms • Nelson, David • Resources September 10, 2016February 20, 2018FXTAS, mRNAs

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.

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.

Abnormalities of Synaptic Plasticity in the Fragile X Amygdala

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • 2015 Grants • 2016 Grants • Chattarji, Sumantra • Disease Mechanisms • National Center for Biological Sciences • Research Grant Results February 22, 2016June 29, 2021amygdala, autism, mGluR, NIH

With a $110,050 grant from FRAXA Research Foundation from 2005-2016, Dr. Sumantra Chattarji at the National Center for Biological Sciences researched how the amygdala is affected by Fragile X syndrome. Results published.

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.