GSK3 Archives • Fragile X Research - FRAXA Research Foundation

Drug Tolerance is Likely Culprit Behind the Failure of MGluR5 Clinical Trials

FRAXA Research Foundation Bear, Mark • Massachusetts Institute of Technology (MIT) • McCamphill, Patrick • Research Updates November 19, 2019AFQ056, autism, drug tolerance, GSK3, lithium, mGluR, mGluR5, Novartis, Roche

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.

Pharmacological Tolerance in the Treatment of Fragile X Syndrome

FRAXA Research Foundation 2018 Grants • 2019 Grants • Bear, Mark • Current Research Grants • Massachusetts Institute of Technology (MIT) • McCamphill, Patrick • Treatment Targets May 9, 2018November 19, 2019AFQ056, arbaclofen, drug tolerance, GABA, GSK3, lithium, mGluR5, Novartis, Roche

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.

Altered Neural Excitability and Chronic Anxiety in a Mouse Model of Fragile X

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • 2016 Grants • Completed Research Grant • Disease Mechanisms • Scripps Research Institute • Treatment Targets • Vanderklish, Peter September 13, 2017January 16, 2019AMPK, ERK, GSK3

With a $35,000 grant from FRAXA Research Foundation in 2016, Dr. Peter Vanderklish at Scripps Research Institute, and colleagues, explored the basis of anxiety in Fragile X syndrome.

Repurposing Available Drugs to Treat Fragile X Syndrome – FRAXA Initiatives

Michael Tranfaglia, MD Drug Repurposing • Research Updates February 10, 2017July 26, 2018arbaclofen, autism, baclofen, FRAXA-DVI, glutamate, GSK3, Healx, hypersensitivity, lithium, lovastatin, MAP1b, matrix metalloproteinase, metformin, mGluR, minocycline

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

Targeting AMP-Activated Protein Kinase Pathway in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • Biomarkers • Completed Research Grant • Scripps Research Institute • Treatment Targets • Vanderklish, Peter September 13, 2015April 25, 2018AMPK, FDA, GSK3, metformin, mGluR, mTOR, PDE4

With a $100,000 grant from the FRAXA Research Foundation in 2015, Dr. Peter Vanderklish explored a novel strategy to treat Fragile X syndrome: AMPK activators. The good news is that there are FDA approved (for example, metformin) and naturally occurring AMPK activators (such as resveratrol, found in red wine).

Bryostatin Restores Learning and Memory in Adult Fragile X Mice

FRAXA Research Foundation Research Updates March 11, 2015July 23, 2018Alzheimer's, BDNF, cancer, FRAXA-DVI, GSK3, PSD-95

Just as the Amazon rainforest may hold a cure for cancer if only scientists can find it, a bizarre marine critter found off the California coast — Bugula neritina— is the only known source of a potential new Fragile X treatment, Bryostatin. Last month, FRAXA sat down with scientists from Neurotrope BioScience, a specialty biopharmaceutical company developing medicines for rare diseases and Alzheimer’s based on Bryostatin. Their Fragile X program is based on research by a West Virginia team led by Daniel Alkon, MD, which showed that Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult Fragile X mice. “Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacologic treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat Fragile X mental retardation even after postpartum brain development has largely completed,” remarked Dr. Alkon. Bugula and Bryostatins Often mistaken for seaweed, bugula is actually colonies of small animals, likeRead more

Glycogen Synthase Kinase-3 (GSK3), Lithium and Fragile X

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • Has Results • Jope, Richard • King, Margaret • Treatment Targets • University of Miami • Yuskaitis, Christopher September 12, 2013November 14, 2019autism, GSK3, lithium, mGluR5

With $208,000 in funds from FRAXA Research Foundation, Dr. Richard Jope and his team at the University of Miami tested whether newly developed, highly specific inhibitors of GSK3 can reduce behavioral abnormalities in Fragile X mice.

What Works, and What Doesn’t

Michael Tranfaglia, MD Research Updates September 7, 2012June 21, 2018Alzheimer's, AMPAkines, autism, BK channel, cancer, ERK, GABA, GSK3, lithium, mGluR5, minocycline

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

Small Molecule Modulators of Lithium for Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Completed Research Grant • Haggarty, Stephen • Harvard University • Massachusetts Institute of Technology (MIT) • Reis, Surya • Treatment Targets February 1, 2010August 9, 2018autism, GSK3, iPS, lithium

With a $219,500 grant from FRAXA Research Foundation, Dr. Stephen Haggarty from Havard/MIT developed a high-throughput drug screen to find compounds that inhibit GSK3, a critical enzyme in Fragile X. He looked for compounds that can accomplish this either alone or in combination with lithium, offering the possibility of enhancing the effectiveness of lithium as a treatment. His drug screen used patient-specific neural progenitor (NP) cells derived from human induced pluripotent stem cells (iPSCs) – which are created from cells in a skin biopsy from people with Fragile X syndrome (FXS) and other autism spectrum disorders.

Transgenic Mouse Models of Fragile X Syndrome

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • Bauchwitz, Robert • Columbia University • Completed Research Grant • Disease Mechanisms February 13, 2006August 13, 2018GSK3, mGluR5

With $736,000 in grants from FRAXA Research Foundation over 2000-2007, Dr. Robert Bauchwitz at Columbia University developed 15 transgenic mouse models of Fragile X syndrome, using them to evaluate a range of experimental treatments. Results published.