Novel Modulators of Potassium Channels to Treat Fragile X

Novel Modulators of Potassium Channels to Treat Fragile X

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.

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Newly Discovered Regulatory Pathways in Fragile X

Newly Discovered Regulatory Pathways in Fragile X

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.

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Sensory Hypersensibility in Fragile X Syndrome and BK Channel Openers

Sensory Hypersensibility in Fragile X Syndrome and BK Channel Openers

With $366,100 in grants from FRAXA Research Foundation, these investigators at the University of Orleans studied sensory abnormalities in Fragile X mice and test the ability of a class of drugs, BK channel openers, to rescue these abnormalities.

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FRAXADev – Developing BK Channel Openers for Fragile X Syndrome

FRAXADev – Developing BK Channel Openers for Fragile X Syndrome
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 theRead more

Fragile X Treatment: New Research Directions

Fragile X Treatment: New Research Directions
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. A synapse showing the axon of neuron 1,Read more

Potassium Channel Modulators to Treat Fragile X

Potassium Channel Modulators to Treat Fragile X

With $246,000 in funding from FRAXA over 2012-2014, the Yale University team of Leonard Kaczmarek, PhD, showed that loss of FMRP leads to an increased Kv3.1 potassium currents and decreased Slack potassium currents in neurons. Both of these changes impair timing of action potentials in auditory neurons (and likely others throughout the brain). The team also found that the firing pattern of 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 and test advanced compounds which may reverse these deficits.

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What Works, and What Doesn’t

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

Channelopathies: Altered Ion Channels in Fragile X Syndrome

Channelopathies: Altered Ion Channels in Fragile X Syndrome

With a $95,000 grant from FRAXA Research Foundation from 2010-2011, Dr. Daniel Johnston and Dr. Darrin Brager at the University of Texas at Austin investigated alterations in ion channels in Fragile X syndrome. They explored potential therapeutic effects of drugs which open and close these channels. Results published.

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The Slack Potassium Ion channel as a Therapeutic Target for Fragile X Syndrome

A paper on this work has been published in Journal of Neuroscience on 2010 August 4: Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b by Leonard Kaczmarek, PhD and Jack Kronengold, PhD Our laboratory has investigated how the excitability of neurons becomes modified in the absence of the FMRP protein. We have found that the levels of two potassium channels, termed Slack and Kv3.1 are altered in mice that lack this protein. We have made significant progress in identifying novel pharmacological activators of the Slack potassium channel for potential therapeutic intervention in FXS individuals. The Slack potassium channel is widely expressed in the brain. Using neurons of the central auditory system, our laboratory has demonstrated that Slack is required for accurate timing of action potentials in response to synaptic stimuli. This channel is activated by the FMRP protein through a direct association

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