GSK3 Archives • Fragile X Research - FRAXA Research Foundation

Scientists Find a New Way to Reverse Symptoms of Fragile X

FRAXA Research Foundation Bear, Mark • McCamphill, Patrick • Research Updates • Senter, Rebecca May 20, 2020May 26, 2020Alzheimer's, amyloid precursor protein, autism, cancer, glutamate, GSK3, hyperexcitability, hypersensitivity, lithium, mGluR, mGluR5, NIH, prepulse inhibition, seizure, TAT (Trans-Activator of Transcription)

FRAXA Investigator and MIT Professor Mark Bear and his colleagues have identified a valuable new target for Fragile X therapeutics: GSK3 alpha. Several FRAXA research teams previously identified GSK3 beta as a treatment target for Fragile X. The catch is that, so far, GSK3 beta inhibitors have proven too toxic for regular use. Dr. Bear’s new discovery opens up the possibility of developing more selective compounds with less toxicity and fewer side effects. Interestingly, lithium inhibits both GSK3 versions – alpha and beta.

Bear lab (Bear 3rd from left, McCamphill on right)

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 • 2020 Grants • Bear, Mark • Current Research Grants • Massachusetts Institute of Technology (MIT) • McCamphill, Patrick • Treatment Targets May 9, 2018May 18, 2020AFQ056, amyloid precursor protein, arbaclofen, baclofen, drug tolerance, GABA, GSK3, lithium, mGluR, mGluR5, Novartis, Roche, seizure

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 Grants • Disease Mechanisms • Scripps Research Institute • Treatment Targets • Vanderklish, Peter September 13, 2017January 16, 2019AMPK, amyloid precursor protein, ERK, GSK3, TAT (Trans-Activator of Transcription)

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, 2017December 26, 2019arbaclofen, autism, baclofen, drug repurposing, ERK, FRAXA-DVI, glutamate, GSK3, Healx, hypersensitivity, iPS, lithium, lovastatin, MAP1b, matrix metalloproteinase, metformin, mGluR, minocycline, NIH, TAT (Trans-Activator of Transcription)

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.

Targeting AMP-Activated Protein Kinase Pathway in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • Biomarkers • Completed Research Grants • Scripps Research Institute • Treatment Targets • Vanderklish, Peter September 13, 2015April 25, 2018AMPK, amyloid precursor protein, ERK, FDA, GSK3, metformin, mGluR, mTOR, PDE4, TAT (Trans-Activator of Transcription)

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).

Peter Vanderklish, PhD, at Scripps Research Institute, FRAXA research grant

Bryostatin Restores Learning and Memory in Adult Fragile X Mice

FRAXA Research Foundation Research Updates March 11, 2015December 26, 2019Alzheimer's, AMPA, AMPAkines, BDNF, cancer, FRAXA-DVI, GSK3, PSD-95, TAT (Trans-Activator of Transcription)

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.

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

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

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, 2012December 13, 2019Alzheimer's, AMPA, AMPAkines, amyloid precursor protein, autism, BK channel, cancer, ERK, GABA, GSK3, lithium, mGluR, mGluR5, minocycline, PAK (p21-activated kinase), TAT (Trans-Activator of Transcription)

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.

Small Molecule Modulators of Lithium for Treatment of Fragile X Syndrome

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

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.

Stephen Haggarty, PhD, Harvard/MIT, Principal Investigator, FRAXA research grant

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 Grants • Disease Mechanisms February 13, 2006August 13, 2018GSK3, mGluR, mGluR5, NIH, seizure

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.