Massachusetts Institute of Technology (MIT) Archives • Fragile X Research

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.

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

Enhancing NMDA Receptor Signaling to Treat Fragile X Syndrome

FRAXA Research Foundation 2018 Grants • 2019 Grants • Barnes, Stephanie • Bear, Mark • Completed Research Grants • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Treatment Targets March 7, 2019May 17, 2020NMDA

Dr. Stephanie Barnes has been investigating the role of NMDA receptors as a FRAXA Postdoctoral Fellow in Dr. Emily Osterweil’s laboratory at the University of Edinburgh from 2016-2018. With an additional year grant from FRAXA, she is now continuing her work to identify novel targets and test pharmacological therapies in the Fragile X mouse model at the Picower Institute at MIT with Dr. Mark Bear.

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, 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.

Mechanisms of Tolerance to Chronic mGluR5 Inhibition

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Bear, Mark • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Osterweil, Emily • Research Grant Results • Senter, Rebecca • Treatment Targets September 19, 2017August 29, 2018AFQ056, drug tolerance, glutamate, lovastatin, mGluR5, NIH, Novartis, Roche

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.

Development of a High-Content Synapse Assay to Screen Therapeutics for Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Bear, Mark • Bhakar, Asha • Completed Research Grants • Drug Repurposing • FRAXA Research Grants • Massachusetts Institute of Technology (MIT) • Treatment Targets September 8, 2017March 30, 2018autism, FDA, mGluR5, NIH

With a $45,000 grant from FRAXA Research Foundation in 2009, Dr. Mark Bear and Dr. Asha Bhakar used High Content Screening (HCS) to develop an assay sensitive to the effect of the FXS genotype. This project was funded in full by NIH after the first year.

Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Theodore Coutilish Bear, Mark • Massachusetts Institute of Technology (MIT) • Research Updates • Senter, Rebecca March 15, 2017December 26, 2019AFQ056, drug tolerance, glutamate, mGluR, mGluR5, Novartis, Roche

Although the clinical trials failed to show efficacy in the patient population and Novartis and Roche discontinued their Fragile X development programs, Dr. Senter has worked with Mark Bear, PhD to carefully review parent observations. Those caregiver reports suggested tolerance to mGlu5 antagonists. Antagonists developed quickly, consistent with some preclinical findings in the mouse model.

Mark Bear’s Goal: Disease-Modifying Treatments for Fragile X

Theodore Coutilish Bear, Mark • Massachusetts Institute of Technology (MIT) • Research Updates September 19, 2016December 26, 2019arbaclofen, autism, mGluR, mGluR5

Researcher Mark Bear, PhD, Picower Professor of Neuroscience, sees success developing disease-modifying treatments for Fragile X syndrome and other developmental brain disorders. Finally, hope. And it comes from his lab, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology.

Lovastatin Discovery in Fragile X Mice Leads FRAXA to Fund Clinical Trials

FRAXA Research Foundation Bear, Mark • Massachusetts Institute of Technology (MIT) • Osterweil, Emily • Research Updates • Treatment Targets June 11, 2013December 13, 2019autism, ERK, Fragile X Meeting, glutamate, lovastatin, mGluR, minocycline

Dr. Emily Osterweil was awarded the FRAXA Pioneer Award at the opening dinner of the 2011 FRAXA Investigators Meeting in Southbridge, MA for her work demonstrating that Lovastatin could treat Fragile X. Dr. Osterweil conducted her experiments in the MIT laboratory of Dr. Mark Bear and has since established her own laboratory at the University of Edinburgh. The team discovered that lovastatin, a drug widely prescribed for high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent epileptogenesis. The work is published in the prestigious neuroscience journal Neuron: Lovastatin Corrects Excess Protein Synthesis and Prevents Epileptogenesis in a Mouse Model of Fragile X Syndrome.

Role of Excessive Protein Synthesis in the Ontogeny of FXS

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • Bear, Mark • Bosch, Miquel • Completed Research Grants • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Treatment Targets May 8, 2011May 16, 2018mGluR, mGluR5, mRNAs

With a $90,000 grant from FRAXA Research Foundation in 2010-2011, Dr. Mark Bear and Dr. Miquel Bosch tested the simple hypothesis that the excessive rate of protein synthesis is not a consequence but the primary cause of the structural alterations occurring in Fragile X syndrome.

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

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

Experimental Compound FRAX486 Reverses Signs of Fragile X in Mice

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • Completed Research Grants • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Tonegawa, Susumu February 13, 2006April 25, 2018PAK (p21-activated kinase)

With an $81,000 grant from FRAXA Research Foundation from 2005-2006, Dr. Susumu Tonegawa and his team at MIT studied the enzyme PAK to determine how it could be used for a treatment target. Results published.