With a $90,000 grant from FRAXA Research Foundation over 2018-2019, Drs. Devin Binder, Iryna Ethell, and Patricia Pirbhoy at the University of California at Riverside aim to understand – and reverse – hypersensitivity to sound in Fragile X syndrome.
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 $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.
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.
Cures Within Reach, the leading global nonprofit focused on repurposing research as a fast track to saving patient lives, has awarded FRAXA Research Foundation the 2017 Golan Christie Taglia Patient Impact Philanthropy Award for efforts to find treatments for the rare disease Fragile X syndrome.
FRAXA Research Foundation was founded in 1994 to fund biomedical research aimed at finding a cure for Fragile X syndrome and, ultimately, autism. We prioritize translational research with the potential to lead to improved treatments for Fragile X in the near term. Our early efforts involved supporting a great deal of basic neuroscience to understand the cause of Fragile X. By 1996, these efforts had already begun to yield results useful for drug repurposing. To date, FRAXA has funded well over $25 million in research, with over $3 million of that for repurposing existing drugs for Fragile X. Here are some examples of FRAXA-funded work on repurposing available drugs for Fragile X syndrome: Lithium In the mid-1990s, the Greenough lab at the University of Illinois discovered that FMRP, the protein missing in Fragile X, is rapidly translated in dendrites in response to stimulation of glutamate receptors. FRAXA funded preclinical validation of this discovery in theRead more
Jean-Francois Lepage, PhD, and Francois Corbin, MD, PhD, with MRI machine If all the science world’s a stage, Fragile X researchers are more than merely players. They are center stage. So believes Francois Corbin, MD, PhD, professor, Université de Sherbrooke, Canada, who directs the university’s Fragile X Clinic. Corbin, who has received more than $100,000 in FRAXA support since 2012, is leading a pilot randomized Phase II trial, exploring the tolerability and the synergistic effect of a combined therapy. They will combine minocycline, which is often used to treat acne, and lovastatin, which is used to lower cholesterol. Both drugs target specific alterations in the brain of Fragile X patients that would potentially have a combined powerful effect on their behavior. “To my knowledge, this is the first time we have a clinical trial with two different drugs combined to act on two different targets,” Corbin said. “The combined actionRead 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
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
A major article from the Ethell lab at UC Riverside has shown the therapeutic potential of drugs that inhibit the enzyme MMP-9. A nice lay description of the new paper is here and the abstract of the article is here. Dr. Ethell was awarded FRAXA Research Foundation funding from 2008-2011 and 2012-present. This latest work shows that human Fragile X tissues have elevated levels of the extracellular enzyme MMP-9, as well as an increase in the active fraction of that protein (like most enzymes, MMP-9 can exist in an inactive form which can be switched on rapidly; this kind of regulation is important in most biological pathways.) The Ethell lab also showed that genetic reduction of MMP-9 rescues most Fragile X phenotypes in the mouse model. Previous work had shown that inhibition of MMP-9 with minocycline also had similar effects, but minocycline has many different actions. These experiments demonstrate conclusively that MMP-9 inhibition is the activeRead 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
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
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.
With a $157,000 grant from the FRAXA Research Foundation in 201202013, Dr. Kendal Broadie and Dr. Cheryl Gatto worked to define the distinct but also overlapping roles for MMP-1 and MMP-2 in synaptic structural and functional development. In drug studies with Fragile X fruit flies, they will be testing a range of MMPIs in drug treatments to compare effectiveness during development and at maturity, in order to define the contributions of FXS developmental impairments and adult recovery/plasticity.
Available Medication Lovastatin Corrects Excess Protein Synthesis in Fragile X Mice Dr. Emily Osterweil At the opening dinner of the 2011 FRAXA Investigators Meeting in Southbridge, MA, Dr. Emily Osterweil was awarded the FRAXA Pioneer Award for work demonstrating that Lovastatin could treat Fragile X. Dr. Osterweil conducted her experiments in the MIT laboratory of Dr. Mark Bear; she has since established her own laboratory at the University of Edinburgh. The team discovered that lovastatin, a drug widely prescribed for high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent epileptogenesis. The work is published in the prestigious neuroscience journal Neuron: Lovastatin Corrects Excess Protein Synthesis and Prevents Epileptogenesis in a Mouse Model of Fragile X Syndrome. One implication of the mGluR theory of Fragile X is that there are exaggerated consequences of activation of signaling pathways which link metabotropic glutamate receptors (mGluRs) to the cellular machinery ofRead more
Khaleel Razak, PhD – University of California, Riverside with Iryna Ethell, PhD Co-Principal Investigator FRAXA Awards: $45,000 in 2016 $45,000 in 2013 $45,000 in 2012 2013 Update by Khaleel Razak, PhD The goals of our FRAXA-funded research project are to determine robust biomarkers relevant to the FXS and to examine the efficacy of minocycline treatment. We particularly focus on the symptoms related to communication from both production and reception viewpoints. We have identified multiple biomarkers in the Fmr1 knockout (KO) mice with the first year’s funding. There is a deficit in ultrasonic vocalizations (USV) in the KO mice. When male mice are paired with females, the KO males call at significantly slower rates (Rotschafer et al., 2012). Minocycline treatment during the first month of life, reverses the USV deficits. Based on this promising finding of a potentially useful pre-clinical outcome measure, we have pursued identification of critical developmental time windows
Question: How Do Families Decide Which Trial is Best for Them? Answer: Each of the trials has different requirements for joining, so many – if not most – people will only be eligible for one trial after screening. The best way to approach this is to call the clinic contact closest to your area and discuss this with him/her. Age, weight, current medications, behavior, and IQ are all factors. When will the Trials be Finished? It all depends on enrollment. Trials need to have a certain number of people (a number determined before the trial starts) complete the trial before they can analyze the data and present results to the FDA. It all depends on how many people sign up to participate. Is There Assistance for Travel? Many trials provide financial assistance for travel expenses. The amount depends on how far you have to travel. Please check with the coordinatorRead more
At the start, it’s always hard to know what methods will work best for something as complex as the development of disease-modifying treatments for Fragile X. But, we’ve always tried to let the science lead us down the right path. At this point, the results are unequivocal, and they have shaped how we are looking for the Next Great Thing in Fragile X treatments. As a bit of background, it’s worth noting that there are two basic ways of approaching treatment research for any disease: rational drug discovery vs. high-throughput screening. Rational drug discovery means exploring the basic mechanism of disease and identifying specific “treatment targets” that might be expected to correct the underlying problem. Usually, the target is an enzyme (a protein which facilitates biochemical reactions in the cell) or a receptor (a protein, usually on the cell surface, which detects small amounts of a chemical messenger, such asRead more
Treatment Trials As you probably know, three pharmaceutical companies are conducting clinical trials in Fragile X. Two Swiss giants, Novartis and Roche, are racing to get their lead mGluR5 antagonists to market, and U.S. startup Seaside Therapeutics is pursuing a compound which targets the brain receptor, GABAB. Novartis has large-scale Phase IIb/III trials of the drug AFQ056 well underway. Sites worldwide are enrolling adolescents and adults, with 35 more adults needed and recruitment of adolescents planned through Fall 2012. At this point, some participants have already completed the placebo-controlled trial and are now taking AFQ056, with the option of continuing it until it reaches the market. Novartis is also working toward a trial of AFQ056 for younger children with Fragile X. Roche completed a Phase II trial of its mGluR5 antagonist (currently with the catchy name of RO4917523) last year and is about to commence a larger Phase II trialRead more
On the eve of Thanksgiving, we want to thank everyone who has helped bring us so close to available treatments - and to take stock of where we are. by Michael R. Tranfaglia, MD Medical Director and Fragile X Parent Each year, we’ve described ever greater progress toward our ultimate goal: disease-modifying treatments and an ultimate cure for Fragile X. At times it must seem that this quest will take forever; however, the pace of research has truly moved into high gear in 2011! While FRAXA’s mission to find a cure for Fragile X is simple in concept, it is clearly a daunting task. To address the overwhelming complexity of this challenge, we have developed a plan of attack: • We fund high-quality basic research on the causes of Fragile X, which leads to possible treatment strategies (therapeutic targets). • We fund some of the finest neuroscientists in the worldRead more
Results of the First Clinical Trial of Minocycline in Fragile X Patients were Published Today, and They Suggest That This Medication can Improve Challenging Behaviors Commonly Seen in Fragile X. Twenty males and females with Fragile X, ages 13-32, participated in this open-label add-on trial at the Fragile X clinic in Toronto, Canada. Dr. Carlo Paribello, himself father of two boys with Fragile X, led the trial which was funded by FRAXA. Patients received either 100 mg or 200 mg of minocycline daily, and their behaviors were evaluated prior to treatment and again 8 weeks after daily minocycline. Behavioral scores showed striking improvement and the drug was generally well tolerated. The most significant side effect noted was, in blood tests, an asymptomatic seroconversion to a positive ANA in two people. This is a nonspecific marker of immunoinflammatory connective tissue diseases, so physicians who prescribe minocycline should be aware of itsRead more
With a $220,000 grant from FRAXA Research Foundation over 3 years, Dr. Iryna Ethell from the University of California at Riverside studied the regulation of dendritic structure by matrix metalloproteinases and other extracellular signaling pathways. This work identified a major treatment strategy for Fragile X with the available MMP-9 inhibitor, minocycline.
Three Researchers Honored at FRAXA 2008 Investigators Meeting Over 150 scientists from around the globe gathered in Durham, New Hampshire, for FRAXA Research Foundation's Investigators Meeting on September 21-24, 2008. They came from Australia, Canada, India, Turkey, the U.S., and eight European countries. Their common goal: "to share, collaborate and publish," in the words of FRAXA's Medical Director, Michael Tranfaglia, MD, to find effective treatments and a cure for Fragile X, the foremost inherited cause of mental retardation and autism. Most of the attendees were university-based professors, postdoctoral fellows, and graduate students who have FRAXA research grants. Also participating in the meeting were scientists from the National Institutes of Health (NIMH, NICHD, and NINDS), Neuropharm Group PLC, Hoffman LaRoche Inc., GlaxoSmithKline, Indevus, and Seaside Therapeutics, as well as 20 parents of Fragile X children. At the opening reception, FRAXA honored three investigators for taking extraordinary steps to advance research: FRAXARead more
Study leader Iryna Ethell awarded FRAXA Breakthrough Award for 2008 A University of California Riverside team of scientists has found that an available drug called minocycline, used widely to treat acne and skin infections, might also be used to treat Fragile X. The study’s findings have already led to the approval of a FRAXA-funded clinical trial in Toronto, Canada, that will test minocycline in patients with Fragile X. Neurons in the brain communicate with each other at specialized contact sites called synapses, with many of these synapses occurring on small mushroom-shaped structures called dendritic spines. During early development dendritic spines have immature finger-like shapes. But learning stabilizes the synapses and dendritic spines take on a mature mushroom shape, which make them more efficient. The brains of patients with Fragile X syndrome have an overabundance of immature dendritic spines. In their report, the researchers, led by Iryna Ethell and Douglas Ethell,Read more