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
FRAXA Research Foundation will fund over $1 million in research aimed at finding new and improved treatments — and ultimately a cure — for fragile X syndrome. Research applications are due February 1, 2018. Clinical trial proposals are accepted anytime. Every year we receive proposals from scientists worldwide seeking funding for the most cutting-edge fragile X research.
There’s been a lot of press concerning a new biotechnology called CRISPR/Cas9, or simply CRISPR. This technology, which is based on the discovery of naturally-occurring bacterial defense mechanisms, has attracted an enormous amount of biotech investment. It has also excited the imaginations of scientists, clinicians, and rare disease advocates everywhere. How might CRISPR be applied to Fragile X syndrome? CRISPR offers the tantalizing possibility of “editing” genes very precisely, and it could (theoretically) excise the methylated trinucleotide repeat sequence from Fragile X cells, rendering them entirely normal. CRISPR: A Developing Technology First, it is important to understand that this is a developing technology. CRISPR is a powerful new research tool for editing genes; it can be used to enhance gene therapy approaches in vitro (in a dish in the lab), and to knock out genes quickly and easily. To date, its biggest advantage is the speed and cost-effectiveness with whichRead more
A number of people have asked us about FRAXADev, a new project starting in France; this is a nonprofit initiative which seeks to develop a new kind of drug for fragile X. The drugs they are interested in testing in fragile X clinical trials were developed by Bristol-Myers Squibb many years ago, and are now off patent. This class of drugs opens a potassium channel in the membrane of neurons, which helps to decrease neuronal excitability. These agents are called “BK Channel Openers”. The project is seeking donations to this effort, but they are not a 501(c)3 tax-exempt organization, so for US residents this is mostly a “crowdfunding” appeal at this point. There are a few points we’d like to clarify, since so many people are asking: FRAXADev isn’t part of FRAXA Research Foundation; these are two completely different organizations. The research team was originally funded by FRAXA, but the
Metadoxine for Fragile X – a glimmer of hope Alcobra just announced results from their trial of a proprietary formulation of metadoxine in Fragile X Syndrome subjects, and there is a glimmer of hope in their announcement http://www.alcobra-pharma.com/releasedetail.cfm?ReleaseID=919218. While the drug did not show any beneficial effect on the primary outcome measure (essentially, an ADHD scale) it did result in some statistically significant improvement on 2 secondary measures. One of those showing improvement, a subscale of the Vineland Adaptive Behavior Scale (VABS) which measures daily living skills, is a well validated outcome measure which has been used in other Fragile X trials (though none of the other drugs resulted in improvement.) The other outcome measure showing improvement was the KiTAP distractibility test. In both cases, the improvement was not only statistically significant, but also likely clinically meaningful; in other words, it was a relatively large effect. The folks at Alcobra rightly note that this is the best showing to
Fragile X Presentation by Michael Tranfaglia, MD, FRAXA Medical Director IDD-C conference – Stanford University – April 21, 2015 In-depth discussion of how research brought us to the point of clinical trials, the problems encountered in recent trials, and where we go from here. Dr. Tranfaglia presents new ideas on Fragile X disease mechanisms and new treatment strategies which may address these. Presentation: 1 hour, Q&A: 20 minutes.
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. Work over the next few years led to the mGluR
Promising results in Phase 2 clinical trial by Michael Tranfaglia, MD FRAXA Medical Director This isn’t a Fragile X trial, but the Neuren compound, NNZ-2566, that is in trials now for Fragile X has shown significant positive effects in a Phase 2 trial for Rett syndrome. The results of the trial are interesting, in that improvement was seen a Rett syndrome-specific rating scale compared to placebo, and there was also improvement noted on the CGI-I (Clinical Global Impression of Improvement) and Caregiver Top 3 Concerns. However, there was no effect seen on ABC scores (Aberrant Behavior Checklist) compared to placebo. Many in the Fragile X field have noted the inadequacies of the ABC; indeed, it was never designed or intended to be an outcome measure for clinical trials. In this case, a Rett-specific rating scale called the Motor-Behavior Assessment (MBA) showed a statistically significant and clinically meaningful treatment effect at the
Roche has shared the sad news that their clinical trials in Fragile X have been unsuccessful. They will host a Webcast on Thursday, September 18, from 12:30pm – 1:30pm (EDT) to explain the results. For details and dial-in information please see this letter from Luca Santarelli, the Head of Neuroscience, Ophthalmology and Rare Diseases at Roche Pharma Research and Early Development on Roche`s Research Program on Fragile X. After the webcast, FRAXA will post a Q&A about what we’ve learned, other clinical trials in progress, and other promising treatment strategies.
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
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
Many older family members in the fragile X community are affected by FXTAS (Fragile X-associated Tremor/Ataxia Syndrome). We all hope that knowing the underlying cause of neurodegenerative symptoms in FXTAS will help in the development of specific treatments over the long term. In the short term, we would also hope that having a specific diagnosis would help us to identify particular available treatments which might be more effective than others. One of the available treatments for Alzheimer's Disease is a glutamate receptor blocker called memantine (Namenda), and dementia specialists think this drug could be effective in treating a wide range of neurodegenerative diseases. It has been found to be effective in treating Lewy Body Dementia, a disorder which causes parkinsonism and cognitive decline, with features rather similar to FXTAS. This led researchers to think that this drug could also be useful in treating FXTAS, and initial open-label experience with it wasRead more
It's Official: Fragile X is Now the Hottest Research Topic in All of Neuroscience! Just last month, massive publicity attended the publication of Fragile X clinical trial results and major papers by FRAXA’s outstanding translational researchers. Even as news of the first round of Fragile X clinical trials is emerging, Phase III trials (which can lead to actual marketing of medications) are under way and slated to finish around the end of the year. This is exciting, and it is just the tip of the iceberg. Thanks to your support, FRAXA has developed an entire pipeline of disease-modifying treatments for Fragile X. We started years ago by funding basic research to understand the cause of Fragile X; we then recruited dozens of the world’s finest neuroscientists to look for ways to fix the underlying problems. Many promising treatment strategies have emerged. Some are existing medications that no one imagined wouldRead 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
A study finds that a new compound reverses many of the major symptoms associated with Fragile X syndrome (FXS). The paper is published in the April 12 issue of the journal Neuron, describes the exciting observation that the FXS correction can occur in adult mice, after the symptoms of the condition have already been established. Previous research has suggested that inhibition of mGlu5, a subtype of receptor for the excitatory neurotransmitter glutamate, may ameliorate many of the major symptoms of the disease. This study, a collaboration between a group at Roche in Switzerland, led by Dr. Lothar Lindemann, and Dr. Mark Bear’s MIT lab, used an mGlu5 inhibitor called CTEP to examine whether inhibition of mGlu5 could reverse FXS symptoms. The researchers gave CTEP to mice which model Fragile X. "We found that even when treatment with CTEP was started in adult mice, it reduced a wide range of FXSRead 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 world