With a $90,000 grant from FRAXA Research Foundation, Dr. Patrick McCamphill and Dr. Mark Bear at Massachusetts Institute of Technology (MIT) will further investigate drug tolerance and ways to overcome it.
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.
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.
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.
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.
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).
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.
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.
Elizabeth M. Berry-Kravis, MD, PhD has informed us that Rush University Medical Center in Chicago is enrolling the first patient in the NeuroNext learning trial for children ages 3-6 this week. This is the start of a large-scale Fragile X clinical trial of Novartis AFQ056 (an mGluR5 antagonist) with children.
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.
Rush University Medical Center Professor Elizabeth M. Berry-Kravis, MD, PhD, Begins a Large-Scale Clinical Trial to Study Effects of AFQ056, an mGluR5 Blocker, on Learning in Young Children BERRY tenacious! You can say a lot about Elizabeth M. Berry-Kravis, MD, PhD: • University of Notre Dame and University of Chicago educated. • Professor of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center. • Board certified in neurology with a special qualification in child neurology. • Expert in Fragile X syndrome and other neurogenetic diseases. You can also say she’ll talk your ears off. Literally! And much of it may go over your head. Yes, she often talks in industry jargon. Plenty of it. OK, we get it. She’s smart. Super smart. She’s caring. Super caring. She’s knowledgeable. Super knowledgeable. But did you know she’s tenacious? Incredibly, super-duper, berry tenacious? Good thing for us she’s on our side. No doubt herRead more
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
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
2016 Funding Priorities Start with Clinical Trials While FRAXA Research Foundation’s research goals remain largely unchanged, the landscape in which we operate has changed significantly in the past few years. Negative results from the major clinical trials of investigational agents have resulted in cessation of development of mGluR5 antagonists for Fragile X syndrome. There is still much evidence that this drug class could be successful as a Fragile X therapeutic, but we do not see the need for more “proof of principle”-type preclinical research on mGluR5 antagonists. Studies of possible mechanisms of tolerance in Fragile X would be appealing as a topic going forward, as would studies of circuit function in Fragile X, since available evidence suggests some form of circuit-based (rather than synaptic) tolerance in Fragile X mice and humans. Other potential areas of interest would include exploration of combination treatment strategies, both in animal models and in clinicalRead more
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
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.
Drug Tolerance and Dose Range Problems May Have Been the CulpritsAndy Tranfaglia and his dad, Mike Tranfaglia In my opinion, the Fragile X clinical trials of AFQ056 sponsored by Novartis failed because of a dose range that was inadequate for Fragile X, and because of the unexpected development of tolerance. Dosage problems are relatively easy to correct, but tolerance to the degree we observed may be a kind of fatal flaw, at least if we're talking about mGluR5 antagonists. The mGluR Theory of Fragile X is still probably correct; it's just that no one (least of all Novartis) expected tolerance to this drug -- indeed, I'm not sure they would agree that's what happened. I think we saw a much better response than most people because our son, Andy, was also on minocycline, effectively augmenting the response, and perhaps delaying the development of tolerance. This may be a clue to understanding the mechanism of tolerance,Read more
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 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
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
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
Funding Priorities for 2014 Grant Cycle We anticipate particularly keen competition for funding in this grant cycle. Challenging economic times inevitably force us back to fundamental principles, and so our overall priorities for 2014 grants will be to bring new, high-quality scientists into the Fragile X field, and to promote translational, preclinical, and clinical research with the greatest chance of improving therapeutics for those living with Fragile X. Here are a few key implications of these policies: We want new ideas! The mGluR Theory is now being tested in the clinic; we do not anticipate funding any major new projects investigating mGluR5 function, although there are many possible spin-off projects which could be the basis for successful applications. Likewise, we do not assign a high priority to studies of every element of mGluR-coupled signaling pathways, unless the topic of study is an especially druggable target. Most components of signaling pathways inRead more
Complete Phase II/III Clinical Trials of mGluR5 Antagonists – and learn results Currently two large pharmaceutical companies – Novartis and Roche – are conducting large-scale clinical trials of experimental new medications for Fragile X syndrome which target the mGluR5 pathway. The Novartis trial has finished enrolling adults and adolescents, while a pediatric trial is set to begin soon. The Roche trial is well on the way to completion as well, but is still enrolling some age groups. FRAXA has been working diligently to educate families about these trials in the hopes of getting them completed as quickly as possible. Our goal (of course) is to discover whether these new drugs could be effective treatments for Fragile X, and to see these trials through to marketing of mGluR5 antagonists for Fragile X. Accelerate Clinical Trials of Investigational Treatments, based on research already funded by FRAXA New treatment strategies have emerged and
Two new papers from FRAXA-funded researcher Dr. Richard Jope demonstrate the potential of GSK3 inhibitors, including the available drug, lithium, to reverse learning deficits in Fragile X. Dr. Jope has previously shown that lithium and other more specific inhibitors of the enzyme Glycogen Synthase Kinase 3 (GSK3) can rescue key symptoms in Fragile X mice. These new publications take that study a step further by showing that lithium (at usual therapeutic doses) and investigational GSK3 inhibitors could reverse a number of cognitive deficits in the mice. The Jope group showed that Fragile X mice are abnormal in novel object recognition, spatial memory, and temporal order memory, and that these GSK3-inhibiting compounds could all reverse these defects, along with associated electrophysiological abnormalities. Furthermore, in the short term, these abnormalities were relatively insensitive to treatment with an mGluR5 antagonist (although other studies suggest that prolonged treatment with mGluR5 antagonists can correct these abnormalities indirectly).Read more
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.