Finding a Cure for Fragile X
Thirteen centers across the US enrolled children with Fragile X in a large-scale clinical trial of Novartis AFQ056. Dr. Elizabeth Berry-Kravis and colleagues aim to show that this targeted treatment — an mGluR5 blocker for Fragile X which failed in previous adult human trials — can be better evaluated by studying effects on learning in young children.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Read moreThis 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!
Read moreNovartis 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.
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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.
Read moreQuestion: 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.
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With $184,000 in funding from FRAXA Research Foundation from 1996-2005, Dr. Ben Oostra and his team at Erasmus University have done multiple studies related to Fragile X syndrome. This lab created the first Fragile X mouse models and went on to perform many critical studies in Fragile X mouse models. Results published.
Read moreWith a $120,000 grant from FRAXA Research Foundation over 2008-2009, Drs. Oostra and deVrij at Erasmus University studied miRNA and Fragile X. miRNAs are RNAs that can repress the translation of target mRNAs – therefore they can play a role in protein synthesis within the neuron. Preliminary results showed large differences in miRNA expression in the Fragile X mouse brain compared to the wild type. This lab investigated the effect of mGluR5 antagonists on the levels of these specific miRNAs.
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