Drug Tolerance is Likely Culprit Behind the Failure of MGluR5 Clinical Trials

Drug Tolerance is Likely Culprit Behind the Failure of MGluR5 Clinical Trials

We have long suspected that the clinical trials of mGluR5 blockers from Novartis and Roche failed because the drug triggered tolerance, losing effect over time. With a $90,000 grant from FRAXA, Dr. Patrick McCamphill, a Postdoctoral Fellow in the MIT lab of Dr. Mark Bear, is investigating. He does indeed find tolerance, and now he is looking for ways to overcome it.

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Novel Modulators of Potassium Channels to Treat Fragile X

Novel Modulators of Potassium Channels to Treat Fragile X

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.

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Coffee, Tea, and Chocolate: Adenosine Receptors in Fragile X

Coffee, Tea, and Chocolate: Adenosine Receptors in Fragile X

Caffeine is the most popular smart drug in the world. With a $90,000 grant from FRAXA Research Foundation, Alberto Martire, PhD and Antonella Borreca, PhD in Rome, Italy are investigating adenosine receptors antagonists to treat Fragile X syndrome. Compounds which are able to block adenosine receptors are commonly found in tea, chocolate, and coffee.

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Pharmacological Tolerance in the Treatment of Fragile X Syndrome

Pharmacological Tolerance in the Treatment of Fragile X Syndrome

With a $90,000 grant from FRAXA Research Foundation over 2018-2019, Dr. Patrick McCamphill, postdoctoral fellow in Dr. Mark Bear’s lab at Massachusetts Institute of Technology (MIT), is investigating drug tolerance to mGluR5 antagonists, arbaclofen, and other potential Fragile X treatments. He is also exploring ways to overcome it.

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Newly Discovered Regulatory Pathways in Fragile X

Newly Discovered Regulatory Pathways in Fragile X

Studies at Yale University and elsewhere are showing that FMRP plays a significant role in the regulation of potassium channels. Looking forward, potassium channel opener drugs could rescue some symptoms of Fragile X in humans.

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In Their Own Words: Reports From the International Fragile X Workshop

In Their Own Words: Reports From the International Fragile X Workshop

The 18th International Fragile X and Related Neurodevelopmental Disorders Workshop in Quebec, Canada, was a great success, featuring Fragile X much more heavily than any previous meeting in this series! We asked our speakers to summarize their work in their own words. These brief updates from researchers investigating Fragile X.

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

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

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.  

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Defining Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

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

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

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.

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Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Although the clinical trials failed to show efficacy in the patient population and Novartis and Roche discontinued their Fragile X development programs, Dr. Senter has worked with Mark Bear, PhD to carefully review parent observations. Those caregiver reports suggested tolerance to mGlu5 antagonists antagonists developed quickly, consistent with some preclinical findings in the mouse model.

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Mark Bear’s Goal: Disease-Modifying Treatments for Fragile X

Mark Bear’s Goal: Disease-Modifying Treatments for Fragile X
Massachusetts Institute of Technology Researcher Mark Bear, PhD, Sees Success Developing Disease-Modifying Treatments for Fragile X Syndrome and Other Developmental Brain Disorders Finally, hope. And it comes from the lab of Mark Bear, PhD, Picower Professor of Neuroscience, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology Dr. Bear is building on the “mGluR theory” and applied insights gained by the study of Fragile X and other genetically defined causes of intellectual disability and autism with some success. His goal is to discover and facilitate the development of disease-modifying treatments for Fragile X and other developmental brain disorders. “Neurons in the brain communicate with each other at specialized junctions called synapses,” said Bear, who earned a BS from Duke University and a PhD in neurobiology at Brown University. “Such modifications are the basis for memory storage in the brain, and go awryRead more

Kimberly Huber, PhD, Explores Hyperexcitability in Fragile X Syndrome

Kimberly Huber, PhD, Explores Hyperexcitability in Fragile X Syndrome
Sensory Overload Ever wonder why your child with Fragile X suddenly screams for no apparent reason or jumps and flaps uncontrollably seemingly for hours? You got it: hyperexcitability. But what exactly causes it? And what can fix it? Kimberly Huber, PhD, is working long and hard in her lab to answer those questions. Dr. Huber, professor, Neuroscience, UT Southwestern Medical Center, is seeking to understand how FMRP regulates connections between brain cells, called synapses, and the function of brain circuits, which are several connected brain cells. Her current focus is the study of synapses and brain circuits in the mouse that mediate sensory perception, including perception of touch and sound. She aims to understand the cellular and molecular mechanisms by which loss of FMRP causes hyperexcitable sensory circuits. The goal: to develop targeted therapeutics that can restore normal brain function and reduce sensory hypersensitivity. “Sensory brain circuits are overactive, or hyperexcitable,Read more

Fragile X Treatment: New Research Directions

Fragile X Treatment: New Research Directions
Re-examining the Nature of Fragile X In the wake of negative results from several high-profile clinical trials in Fragile X, we find ourselves questioning many of our previous assumptions about the nature of this disorder. After all, understanding the basic pathology of disease is critical to development of new treatments — this is true across the board, in all branches of medicine. In the early days of Fragile X research, shortly after the FMR1 gene was discovered and the normal protein product of the gene (FMRP) was identified, it was noted that FMRP is an RNA binding protein. Whatever the normal function of this single protein which Fragile X patients lack, it had something to do with RNA metabolism. Since RNA is the template used to make new proteins, this meant that the Fragile X protein is involved in regulating protein synthesis. A synapse showing the axon of neuron 1,Read more

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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Fragile X Clinical Trial: Novartis Trial Results Are In, and They’re Not Pretty

AFQ056 Fragile X Clinical Trial showed Negative Results This year's Gordon Conference just finished, and Novartis presented their results for the first time (though advisors and advocates had been given a private peak months ago.) To say that the trial results for AFQ056 were disappointing would be the understatement of the century! While the company has already announced that the adult and adolescent trials failed to meet their pre-designated endpoints, the numbers looked really bad. This wasn't a case of the drug working, but placebo effects leading to an outcome that wasn't statistically significant; in this case, the effect of the drug was statistically significant, but in the wrong direction! So, what went wrong? The evidence for using mGluR5 antagonists in Fragile X was really strong going into these trials---in fact, about as good as it ever gets. The drug itself was an advanced compound that had been studied extensively.Read more

Novartis Discontinues Development of mavoglurant (AFQ056) for Fragile X Syndrome

Novartis Clinical Trials in Fragile X Ended Novartis has announced that the company will be discontinuing its development program in Fragile X for its lead mGluR5 antagonist, mavoglurant (AFQ056), following negative results in a large international clinical trial in adults (reported in the Fall of 2013) and most recently, in a trial in adolescents. In both placebo-controlled trials, patients taking mavoglurant did not show improvement over placebo in any outcome measures. Novartis has also announced that the current open-label extension phase of the trial will be closed, but patients will be allowed to continue on the medication until their next scheduled clinic visit, or August 29, whichever comes first. No more of the drug will be dispensed to trial participants, but mavoglurant which has already been dispensed will not be recalled. We hope that we, and the greater Fragile X community, can learn from these trials both about why this drugRead more

Functional Interplay Between FMRP and CDK5 Signaling

Functional Interplay Between FMRP and CDK5 Signaling

Yue Feng, PhD — Emory University School of Medicine with Wenqi Li, PhD, Postdoctoral Fellow FRAXA Awards:  $180,000 $45,000 in 2013 renewed for $45,000 in 2014 $45,000 in 2011 renewed for $45,000 in 2012     Weakened synaptic development and synaptic plasticity, as a result of lacking the functional Fragile X protein (FMRP), underlies the intellectual disability in Fragile X Syndrome (FXS). Decades of  investigation established the role of FMRP in binding its mRNA targets and regulating translation in response to neuronal and synaptic activity changes. Exciting discoveries on two receptors, mGluR5 and GABA, signaling in FXS animal models have led to promising therapeutic approaches based on variation of synaptic activity by mGluR5 antagonists and GABA agonists. However, clinical trials only achieved partial reverse of FXS phenotype. Thus, developing additional therapeutic strategies for treating the full spectrum of FXS symptoms are still pressing challenges. The identification of genome-wide  Fragile X protein (FMRP)  target mRNAs by recent discoveries provides important clues

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New Clue to Fragile X and Autism Found Inside Brain Cells

Researchers led by Dr. Karen O’Malley at Washington University School of Medicine in St. Louis have published results of their work on mGluR5 and Fragile X syndrome. FRAXA Research Foundation provided funding for this work from 2009 until 2013. Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells’ volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells. “Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we’re blocking all of this type of receptor, both inside and on the surface of the cell.”  “This should be a factor we consider when we design drugs to target brain cell receptors. Do we want to reach cell surface receptors, receptors inside the cell

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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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Glycogen Synthase Kinase-3 (GSK3), Lithium and Fragile X

Glycogen Synthase Kinase-3 (GSK3), Lithium 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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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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