A study funded by FRAXA in Italy has encouraging results for people with Fragile X: drugs that block adenosine receptors (A2A) reversed signs of Fragile X in a mouse model.
“One of the most intriguing things about this study is that it points to an entire drug class (not just the one drug used) as potentially therapeutic for Fragile X. Many available compounds block A2A receptors, and we know they are safe and effective.
Long-term, but not short-term, treatment with bryostatin-1 — Neurotrope’s lead investigational therapy — arrested such behavioral and cognitive symptoms as hyperactivity, difficulties with daily life activities, and learning and memory deficits in a mouse model of Fragile X syndrome.
Today, Tetra Therapeutics announces the first unequivocally positive phase 2 clinical trial in Fragile X syndrome, press release below. The results do not depend on carving out a subset of patients or post hoc analysis.
FRAXA Research Foundation has awarded $90,000 over 2019-2021 to principal investigator Dr. Jay Gibson and postdoctoral fellow Dr. Andrew Holley at the University of Texas Southwestern Medical Center. They are investigating circuit mechanisms for auditory system dysfunction and drug tolerance in the Fragile X mouse model.
FRAXA Investigator and MIT Professor Mark Bear and his colleagues have identified a valuable new target for Fragile X therapeutics: GSK3 alpha. Several FRAXA research teams previously identified GSK3 beta as a treatment target for Fragile X. The catch is that, so far, GSK3 beta inhibitors have proven too toxic for regular use. Dr. Bear’s new discovery opens up the possibility of developing more selective compounds with less toxicity and fewer side effects. Interestingly, lithium inhibits both GSK3 versions – alpha and beta.
FRAXA Research Foundation has awarded a $90,000 research grant to Dr. Craig Erickson and Dr. Elizabeth Smith at Cincinnati Children’s Hospital to test functional near-infrared spectroscopy (fNIRS), in children who have Fragile X syndrome. fNIRS is safe, non-invasive, and easily-tolerated. It uses light sources and sensors on the scalp to build a heat map of the brain in action.
Jonathan Lovelace, a FRAXA funded Postdoc at UC Riverside, has made some exciting EEG findings over the past few years studying auditory hypersensitivity in mice and therapeutic drug treatments. A big obstacle in FXS research has been establishing reliable, unbiased, and translation relevant biomarkers that can be used to determine the effectiveness of therapies. One of the most important discoveries they have made is the striking similarity in EEG biomarkers between mice and humans.
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.
The NeuroNext learning trial for children with Fragile X syndrome ages 3-6 is open for enrollment. This clinical trial of Novartis AFQ056 (an mGluR5 antagonist) is recruiting at 13 clinical sites across the U.S.
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.
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.
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.
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, with 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.
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, has launched and is recruiting participants for a large-scale clinical trial to study effects of AFQ056, an mGluR5 blocker, on learning in young children.
Researcher Mark Bear, PhD, Picower Professor of Neuroscience, sees success developing disease-modifying treatments for Fragile X syndrome and other developmental brain disorders. Finally, hope. And it comes from his lab, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology.
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.
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.
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.
by Michael Tranfaglia, MD. 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.