In Their Own Words: Reports From the International Fragile X Workshop

In Their Own Words: Reports From the International Fragile X Workshop

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.

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Clinical Trial of Combined Treatment of Minocycline and Lovastatin in Fragile X Syndrome

Clinical Trial of Combined Treatment of Minocycline and Lovastatin in Fragile X Syndrome

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.

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Double Down: Fragile X Clinical Trial Combines Two Available Drugs

Double Down: Fragile X Clinical Trial Combines Two Available Drugs
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

Why Did Fragile X Clinical Trials of mGluR Antagonists Fail?

Why Did Fragile X Clinical Trials of mGluR Antagonists Fail?
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

Fragile X Syndrome Treatment Target: MMP-9

Fragile X Syndrome Treatment Target: MMP-9

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

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Social Behavior as an Outcome Measure for Fragile X Clinical Trials

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

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.

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Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

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.

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Effects of minocycline on vocal production and auditory processing in a mouse model of Fragile X

Effects of minocycline on vocal production and auditory processing in a mouse model of Fragile X

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

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Clinical Trial of Minocycline Promising

Clinical Trial of Minocycline Promising

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 its

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FRAXA Grant to Carlos Paribello, PhD — Fragile X Research Foundation of Canada

FRAXA Awards: $40,000 in 2008 This trial is based on results of another FRAXA-funded study of minocyline in mice, by the Ethell lab at UC-Riverside. Add-On Pilot Trial of Minocycline in Fragile X Report: 12/1/2008 Researchers funded by FRAXA have discovered that a drug called minocycline can reverse structural abnormalities seen in the brain cells of Fragile X mice. Minocycline belongs to a group of antibiotics called synthetic tetracyclines, and it has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections. With a $40,000 grant from FRAXA, Dr. Carlo Paribello and his team at the Surrey Place Centre Fragile X clinic in Toronto, Ontario, are running an open label trial to see if minocycline can improve learning and reduce anxiety and behavioral problems in people with Fragile X. Twenty participants between the ages of 13 and 35 years take minocycline for

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