Finding a Cure for Fragile X
Jessica Haugen and Jeff Eliason received the phone call every parent dreads in October 2012. Their son’s pediatrician told them their son, Larry, then 1, had fragile X syndrome (FXS) and “there’s nothing you can do about it.” The couple reacted similarly to how other newly diagnosed parents receiving these results. Denial. Discouragement. Depression.
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Co-Founder Kathy May Returns after Two Decades to Write Grants. It’s about discovering new forms of treatments to enhance the mental, emotional and social growth of those affected by fragile X. “And there will be a cure,” she said. “FRAXA is the reason for this hope. I have come full circle to FRAXA and feeling more hopeful than I have in many years.”
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According to Dr. Erickson, AZD7325 is a drug that selectively boosts GABA neurotransmission in the brain. GABA is the primary neurochemical in the brain that blocks brain activation. GABA activity is in balance in the brain with Glutamate activity, which is the primary neurochemical that causes brain activation. In fragile X, GABA activity is insufficient and glutamate activity is excessive, likely causing brain activity to be out of balance. AZD7325 attempts to correct parts of this imbalance by boosting the insufficient GABA activity in the brains of people with fragile X
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With a $90,000 grant from FRAXA Research Foundation awarded in 2017, Dr. Clinton Canal targets seratonin receptors. “There are 15 unique serotonin receptors (at least) and many of them impact the function of brain circuits that are impaired in neurodevelopmental and psychiatric disorders,” said Dr. Canal. “Results from this project could guide new drug discovery or drug repurposing for fragile X.”
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“We treated mice with metformin and corrected all the core fragile X deficits. We are optimistic about using metformin in human clinical trials. This is a generic drug with few side effects” says Nahum Sonenberg, PhD, James McGill Professor, Department of Biochemistry, McGill Cancer Center, McGill University.
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“The occurrence and development of events by chance in a happy or beneficial way.” That’s how Lynne E. Maquat, PhD, describes the process of how her research extended to fragile X syndrome to better understand it and ultimately find advanced treatments.
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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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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.
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FRAXA awarded $44,000 to Healx in 2017 for drug repurposing to find new treatments for fragile X syndrome. The results of this study include eight top “hits” which show promise for fragile X. FRAXA is further investigating these hits.
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Johns Hopkins researcher Christina Timmerman, PhD, searches for a less subjective method to determine if a drug is working in patients with fragile X syndrome Many parents of children with fragile X syndrome were crushed when promising drug trials were unexpectedly stopped a few years ago because subjective behavior-based outcome measures did not justify continuing the trials. The strong feelings linger today. If all goes well with Christina Timmerman’s research, future drug trials may be able to continue with additional metrics for assessment, until there are advanced treatments or even a cure for Fragile X syndrome. This will be welcome news to parents. “We hope a more quantitative outcome measure, such as the proposed microRNA biomarker, would allow for a less subjective method to determine if a drug is working or not,” said Dr. Timmerman, Postdoctoral Fellow, Lab of Mollie Meffert, Department of Biological Chemistry, Johns Hopkins School of Medicine.
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FRAXA postdoctoral fellow, Rachel Sare, PhD, and Carolyn Beebe Smith, PhD Our sons with Fragile X Syndrome typically go to bed early and rise early. Sometimes they jump on us while we are sleeping at 3 a.m., excited to start their day. For heaven’s sake, whY, wHY, WHY? The answer may come from Carolyn Beebe Smith, PhD, senior investigator, Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. She is studying why children, in particularly boys, with FXS have problems sleeping. “We know sleep is important for many aspects of brain function,” said Dr. Smith, who received a PhD from the University of London where she studied the chemical pathology of Alzheimer’s for which she was awarded the Queen Square Prize. “In studies of healthy mice, we have shown restricted sleep during brain development can result in long-lasting changes in behavior. We
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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 her
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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 awry
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University of Edinburgh researcher Emily Osterweil, PhD, probes the brain’s biochemistry to correct imbalances We know the “X” in fragile X refers to the X chromosome, but it could just as easily refer to the unknown.Such as why do people with fragile X have an excessive production of new proteins in their brains that lead to imbalances? That question is being dissected in the lab of Emily Osterweil, PhD, chancellor’s fellow, Centre for Integrative Physiology, University of Edinburgh, UK. Dr. Osterweil is using insights from previous experiments to identify new treatment strategies for fragile X. Her goal is to understand the biochemistry of the brain better. She aims to correct those imbalances by making new proteins from existing messenger RNA, to snap neurons into “remembering” what happened to them before. FRAXA Fellowship Awarded May 2016, Renewed May 2017 Enhancement of NMDA receptor signaling for the treatment of fragile X syndrome
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Thomas Maurin, PhD, and Barbara Bardoni, PhD They aim to gain a better understanding of how the brain develops and functions Like snowflakes, people with Fragile X Syndrome are not all alike. Some respond differently to the same drugs, as previous fragile X research has shown. Understanding this phenomena is leading French scientists Barbara Bardoni, PhD, and Thomas Maurin, PhD, to identify new drugs to improve treatments in patients with fragile X. Among the proteins they have identified, some are known to control brain function and development. This has helped identify a set of candidate proteins for which there are pre-existing active chemical compounds that target their activity. Using these compounds in vitro may revert some FXS hallmarks. “Access to different drugs will allow some flexibility in treatment in the future,” Bardoni said. “We’re looking at using different molecules for different patients at different times to be efficient for the majority of
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The University of Texas at Austin researchers Daniel Johnston, PhD, and Jennifer J. Siegel, PhD, explore harnessing nature to improve memory in fragile X mice We all forget things at times. How many times have you misplaced your car keys or forgotten the name of a person you just met? Now think how you would feel if your memory was stunted from birth? Researchers at The University of Texas at Austin know that people with fragile X syndrome have working memory deficits because of a dysfunction with the front part of their brain. What they recently discovered is how a network of neurons is able to, on occasion, compensate for the loss of FMRP (fragile X mental retardation protein) to regain memory function. A Different Approach “We are taking a slightly different approach to treating and potentially curing fragile X,” said Johnston, professor, Department of Neuroscience, College of Natural Sciences,
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Dr. Heather Bowling, Dr. Eric Klann, Dr. Aditi Bhattacharya New York University scientists make progress developing biomarker signatures and cataloging the types of fragile X patients who will most likely benefit from new therapies Take a closer look at your son or daughter with fragile X syndrome. If you meet another child with fragile X syndrome, chances are he/she may seem totally different to you, yet everyone is united under a FXS diagnosis. Discovering the biological reasons behind these differences is key to identifying which children will respond to what treatment. But how do you find the ‘prediction formula’? New York University scientists may soon know. Co-Principal Investigators Eric Klann, professor, NYU Center for Neural Science, and Aditi Bhattacharya, Independent Investigator, Center for Brain Development, inStem, Bangalore and Heather Bowling, PhD, a post-doc fellow, are working together in the second year of a FRAXA-funded study to develop reliable and relevant biomarkers
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Dr. Jonny Lovelace and Dr. Khaleel Razak University of California researchers Khaleel Razak, PhD, and Jonathan W. Lovelace, PhD, explore drug combinations to limit hypersensitivity to sounds in fragile X mice We’ve all been there. Our child with fragile X hears something and becomes excited. Very excited. Hand flapping follows with non-stop jumping and ear-piercing squawking. Nothing helps. No meds. No iPhone. No magic toy. Several minutes go by. Sometimes longer. How many times have you apologized in a grocery store — or restaurant — or at the mall? Wouldn’t it make our lives better if this unpredictable excitability was minimalized or eliminated? That’s the premise behind research being conducted at University of California, Riverside. Principal Investigator Khaleel Razak, PhD, and postdoctoral fellow Jonathan W. Lovelace, PhD, are studying mice genetically altered to mimic the genetic characteristics of humans with Fragile X Syndrome. Their focus is on the mouse brain’s electrical
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It’s rare to find a researcher working on the Big Three — Fragile X Syndrome (FXS), Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). Then again, David Nelson, PhD, is the rare bird. Nelson is a professor of Molecular and Human Genetics, Baylor College of Medicine, and director of Baylor’s Graduate Program in Integrative Molecular and Biomedical Sciences. He has been involved in FXS research since the late 1980s where he helped identify the mutation and the FMR1 gene. These days, researchers in Nelson’s lab at Baylor are studying FXS, FXTAS and FXPOI using mouse models. The goals are to understand which cell/tissue types contribute to these disorders, which genes are involved and what can be done to modify the course of the disorder as a result of these findings. “We are developing mice that will help us determine what tissue type is responsible for
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