Fragile X Clinical Trial on Novartis’s AFQ056 Opens Enrollment

Elizabeth M. Berry-Kravis, MD, PhD has informed us that Rush University Medical Center in Chicago is enrolling the first patient in the NeuroNext learning trial for children ages 3-6 this week. This is the start of a large-scale fragile X clinical trial of Novartis AFQ056 (an mGluR5 antagonist) with children. With funding from the National Institutes of Health through the NeuroNext network, Dr. Berry-Kravis and colleagues aim to show effects of a targeted treatment — the mGluR5 blocker for fragile X that normalizes brain plasticity in fragile X mice but failed in previous adult human trials — can be better evaluated by studying effects on learning in young children.

Dr. Berry-Kravis aims to change the way drugs are developed for fragile X and developmental disabilities in general. This clinical trial will use an innovative, exploratory new design to develop a different way to test treatments: its focus will be on learning and language. If it is successful, this trial can serve as a model for future trials of targeted treatments operating on neural plasticity in fragile X and other neurodevelopmental disorders.

Elizabeth Berry-Kravis, MD, PhD, fragile X researcher

Details about the clinical trial can be found on ClinicalTrials.gov. In October of 2016 Theodore Coutilish wrote about Elizabeth M. Berry-Kravis and the introduction to this trail.

Learn More about AFQ056 for Language Learning in Children With FXS

If all goes well with with this trial, the entire fragile X field will have new tools for future trials of promising new drug treatments.

To find out about enrollment, please contact Katherine J Friedmann, RN at (312) 942-9841 or katherine_j_friedmann@rush.edu

For those who are curious, NeuroNext is an NINDS initiative that has an large amount of money and funds exploratory trials in neurological conditions. They awarded a whopping $11.5 million for this trial!

Read the NeuroNext Grant Announcement

Fragile X Research Grants 2017 Recipients

FRAXA Research Foundation is excited to announce our 2017 Research Grants aimed at finding specific treatments and ultimately a cure for fragile X syndrome. Several of these projects are funded with generous support from our partner organizations: Autism Science Foundation, The Pierce Family Fragile X Foundation, and the Fragile X Research Foundation of Canada.

Over the coming weeks FRAXA will award additional Fragile X Research Grants. We will add them to this page and share updates on Twitter, Facebook and Instagram, so be sure to follow us.

Autophagy is a Novel Therapeutic Target of Impaired Cognition in Fragile X Syndrome

$90,000 Grant
Jingqi Yan PhD, FRAXA Fellow,
and Suzanne Zukin, PhD, Principal Investigator
Albert Einstein College of Medicine
$90,000 Research Grant over 2 Years

Autophagy is a natural process of programmed degradation and recycling of components of cells. It’s the cells’ system of cleaning house. In fragile X syndrome, autophagy seems to be underactive.

Dr. Zukin and colleagues have previously studied a particular “master regulator” protein, the mammalian target of rapamycin complex 1 (mTORC1), and found that it is overactivated in the hippocampus of fragile X mice. Too much mTORC1 leads to too little of the cleanup system (‘autophagy’) and therefore too much of many other proteins.

The Zukin team will examine whether impaired autophagy causes impaired learning in fragile X mice. They will also investigate whether it can explain the differences seen in the structure of spine-like protrusions on dendrites (connections between neurons), which in fragile X mimic an immature morphology (shape). Then they will look for novel therapeutic strategies that target the autophagy pathway to rescue autophagy and learning in fragile X mice.

Correcting Fragile X-associated Deficits by Targeting Neonatal PKCepsilon Signaling in the Brain

$90,000 Grant
Alexandra Marsillo, Graduate Student
Probal Banerjee, PhD,
Principal Investigator
Tatyana Budylin,
FRAXA Fellow
College of Staten Island
$90,000 Research Grant over 2 Years

The Reason for this Study
Fragile X syndrome (FXS) occurs due the silencing of the X-linked gene Fmr1, and it is known that the protein product (FMRP) of the Fmr1 gene controls expression of other proteins. However, it is unclear how the deficiency of FMRP leads to impairments. So far no mechanistic pathway has been found to link FMRP to FXS.

Discovery of FXS-associated Defects at the Molecular Level
Dr. Banerjee’s team is addressing this information gap by studying PKCe, which is one among the many gene products that are regulated by FMRP. By studying fragile X knockout (KO) mice, which lack FMRP, they have observed that PKCe expression is significantly suppressed in a hormone-secreting center of the brain, the hypothalamus, and the cognitive hub, hippocampus, which regulates hypothalamic activity. They also observed suppression of the sociability hormone oxytocin in the hypothalamus. Simultaneously, increased cell-surface localization of an excitation-causing protein, AMPAR, in the hippocampal nerve cells presumably increased anxiety in the KO mice.

Therapeutic Strategy for Permanent Correction of FXS-associated Defects
The scientists have attempted to compensate for suppressed PKCe signaling by treating the KO mice at an early age with the selective PKCe stimulator DCPLA. Quite strikingly, this resulted in a therapeutic correction of oxytocin expression in the hypothalamus, normalization of cell-surface AMPAR localization in the hippocampus, and correction of later-life hyper-anxiety and autistic-like social behavior deficits in adulthood! Thus, for the first time, this project brings the promise of elucidating a pathway that is compromised in the KO mice and uses a therapeutic strategy to correct the signaling pathway shortly after birth. This strategy is likely to correct early neurodevelopment in the brain and thereby afford a global, permanent correction of neuroconnectivity and behavior in the FXS mice.

The impression that fragile X mouse studies do not translate to human therapy is often based on treatments that are offered beyond the point of critical development when the brain can best be nudged to form the right connections. Therefore, it is highly important to conduct preclinical studies such as this during early brain development. Such studies will have a greater likelihood of eventually translating into successful human clinical trials.

Auditory Dysfunction in Fragile X Syndrome, Role for the Sound Localization Pathway

Elizabeth McCullagh, PhD University of Colorado at Denver
$90,000 Grant
Elizabeth McCullagh, PhD
FRAXA Fellow
University of Colorado at Denver
$90,000 Research Grant over 2 Years

This FRAXA research grant will allow Elizabeth McCullagh, PhD and Achim Klug, PhD to investigate whether neural circuits which process sound are altered in fragile X syndrome. There is a specific circuit which allows us to discriminate between competing sound sources, helping us focus on a sound source of interest such as with a conversation partner. This is the aptly named “cocktail party effect”. The team will measure alterations in this circuit in fragile X syndrome. If clear differences are found, they could be used as potential biomarkers for FXS. 

Achim Klug, PhD

Achim Klug, PhD
Principal Investigator

Neural Markers of Cognitive, Language, and Behavioral Deficits in Children with Fragile X

2017 Fragile X Research Grant: Neural Markers of Cognitive, Language, and Behavioral Deficits in Children with Fragile X
$90,000 Grant
Charles A. Nelson, PhD
Principal Investigator
Boston Children’s Hospital
$90,000 Clinical Grant over 2 Years

With this grant, the team will identify and characterize brain-based markers that predict cognitive, language, and behavioral deficits in young children with fragile X syndrome. Using EEG, a low cost, non-invasive technique, they will measure brain activity in response to sensory stimuli, and correlate this with cognitive, language, and behavioral ratings. The brain-based markers can then be used in future fragile X clinical trials as objective measures for targeted outcomes.

Results from this study should facilitate development of targeted drug and behavioral based interventions. While other research groups have used EEG to study subjects with fragile X, this project will work with much younger children at an earlier stage of development.

carol wilkinson

Carol Wilkinson MD, PhD
Postdoctoral Fellow

MicroRNA Mediated Astroglial GLT1 Dysregulation in Fragile X

2017 Fragile X Research Grant: MicroRNA Mediated Astroglial GLT1 Dysregulation in Fragile X
$90,000 Grant
Yongjie Yang, PhD
Principal Investigator
Tufts University
$90,000 Research Grant over 2 Years

Glutamate is the major excitatory neurotransmitter in the brain. Abnormal regulation of glutamate has been implicated in many neuropsychiatric disorders, including autism, schizophrenia, and fragile X syndrome. It is thought that glutamate levels outside of the nerve cells are elevated and causes nerves more “excited” and induces many symptoms in humans with fragile X and also in mice bred to mimic fragile X syndrome.

Much of glutamate metabolism depends on astrocytes, the versatile and abundant cells nestled between all the neurons of the brain. Extracellular glutamate (which floats around in between brain cells) is regulated by one of the most abundant proteins in the brain, the glutamate transporter GLT1, which is expressed mainly by astrocytes. Previous studies from the Yang lab at Tufts University School of Medicine have found that there is a decrease of this critical glutamate transporter GLT1 in fragile X mice.

This group has shown that removing the fragile X protein from astrocytes decreases the astrocytes’ ability to sweep up excess glutamate. They have recently identified a few small RNA molecules called microRNA that are involved in the regulation of GLT1. With the help of this research grant, they are now exploring how these microRNAs changes underlie decreased GLT1 expression. The Yang lab is also testing whether these microRNAs can restore astrocytes’ ability to reduce extracellular glutamate levels, thus hold the potential to become new therapies for fragile X syndrome.

Haruki Higashimori

Haruki Higashimori, PhD
Co-Principal Investigator

Yuqin Men

Yuqin Men, PhD
FRAXA Fellow

Aberrant Insulin Signaling in a Mouse Model of Fragile X

2017 Fragile X Research Grant: Aberrant Insulin Signaling in a Mouse Model of Fragile X
$90,000 Grant
Nahum Sonenberg, PhD
Principal Investigator
McGill University
$90,000 Research Grant over 2 Years
Year 1: $28,125 from FRAXA; $16,875 from FXRFC

Insulin signaling is known to be dysregulated in diabetes and cancer, and has lately been described to be implicated in cognitive dysfunctions in neurodegenerative disorders such as Alzheimer’s disease. Furthermore, dysregulation of insulin signaling might also be associated with autism. Funded by FXRFC and FRAXA research grants, this study will systematically investigate the impact of insulin signaling on autistic-like behaviors, synaptic plasticity, spine morphology and mRNA translation in the mouse model of fragile X syndrome.

Ilse Gantois

Ilse Gantois, PhD
FRAXA Fellow

Drug Repurposing Accelerates Progress Towards Fragile X Treatments

FRAXA Accelerates Progress Towards Fragile X Treatment Through Drug Repurposing

Healx Study Identifies Eight Promising Targets for Validation

While there are over 8,000 rare diseases affecting an estimated 350 million people worldwide, only around 200 of these conditions have effective treatments. Due to the high cost of developing new drugs, rare diseases have historically been less attractive to pharmaceutical companies. Drug repurposing systematically leverages the detailed information available on approved drugs and reduces the time and money needed to deliver safe “new” treatments, but with greater success rates and a potentially more immediate impact on health care. In 2016, FRAXA partnered with Healx (Cambridge, UK) to conduct drug repurposing studies for fragile X based on transcriptional profiling.

There are currently no approved pharmaceuticals for the treatment of fragile X. Some of the more severe symptoms of fragile X are seizures, mood instability and anxiety, attention deficits, aggression and sleep disturbances. For the families affected by fragile X, effective treatment is the key to a healthier, more peaceful family life and a good night’s sleep.

What follows is the story of how FRAXA and Healx collaborate, progress to date and what comes next. While the implications of this study are directly relevant to fragile X, the basic approach is instructive for other rare diseases and the results offer hope in the treatment of autism and related developmental disorders.

Accelerating the Process at FRAXA

The typical timeline for drug development and approval is well over a decade and most drugs fail before hitting the market. “Our translational research efforts have led to many new treatment targets through a process of rational drug discovery,” says Michael Tranfaglia, MD, Medical Director and Co-founder of FRAXA, “however, many of the treatments we have identified are still in development.” Researching drug targets, testing and optimization, clinical testing and approval all take time. All of this is designed to ensure the safety and effectiveness of new drugs.

So how does FRAXA Research Foiundation accelerate the process? First, by supporting and coordinating basic and translational research to understand the molecular basis of the disease and rapidly discover new drug targets. Then by streamlining drug validation through the Fragile X Syndrome Drug Validation Initiative (FRAX-DVI) and sponsoring clinical trials.

Still, families struggling with fragile X need treatments now.

Drug Repurposing: a Collaboration Between FRAXA and Healx

Therefore, FRAXA commissioned Healx to identify potential drugs to repurpose for the treatment of fragile X. “The advanced methods employed in this study represent a completely new approach” says Tranfaglia, “a potential shortcut to finding available drugs which can make a real difference in the lives of people with fragile X”.

Tim Guilliams, PhD, the founder and CEO of Healx explains, “we worked hand in hand with FRAXA, using technology to identify the relevant datasets and perform analysis across many different diseases and data types at large scale. Today there’s a continuous wealth of data being generated about drugs and diseases — scientific papers are being published at an average rate of 2 papers per minute, with tens of millions already available. Analysing this data with natural language processing, advanced analytics and machine learning algorithms is an effective way to identify new links between existing drugs and diseases that might otherwise remain unknown.”

The results are in for fragile X, with the table listing the eight drug candidates recommended for further in vivo investigation either as monotherapies and/or combined with existing medications. Read the complete drug repurposing summary report here. But let’s summarize what exactly was done to identify these drugs and what happens next.

Top 8 Drug Candidates for Fragile X

  • Disulfiram
  • Sulindac
  • Metoprolol
  • Topiramate
  • Phenformin
  • Quercetin
  • Zardaverine
  • Phenformin

The Healx Approach: Transcriptional Profiling

What is transcriptional profiling? Compare this to the process to optimizing bread baking if you were to start with a preexisting mixture of ingredients that is producing flat loaves of wheat bread. You test the mix and find irregular levels of salt and yeast. If you understand the chemistry of baking, you can predict that too much salt or not enough yeast in the dough will result in a flat loaf of bread. Similarly, transcriptional profiling starts with a thorough understanding of the genetic characteristics and biological mechanisms of a disorder, but with a much larger set of variables. This is why FRAXA funds basic research and recruits neuroscientists to investigate the molecular mechanisms of fragile X. “This is an expensive and time-consuming process, but it has been quite successful” says Tranfaglia.

Creating a Disease Signature for Fragile X

First, Healx profiled the symptoms of fragile X to identify the characteristics of a treatment that would most improve patients’ quality of life — drugs that increase cognition, alleviate seizures, and moderate mood and behavior. Healx took into account all that is known about genes and biological pathways associated with fragile X. Next they identified the characteristics of an ideal drug target, through what Healx calls Drug-Gene Expression Matching (DGEM).

Finding Drugs that Match the Signature

To continue the bread analogy, this is comparable to searching a catalog of baker’s ingredients for ones that balance out salt and yeast. Similarly, Healx leveraged the huge amount of data available in public and proprietary datasets to computationally search for drugs for fragile X. They looked at the genes over- or under-expressed in fragile X compared to a typical genome and compared them with the profiles of drugs from Healx’s database. Then they predicted that drugs with the opposite profile of the disease would be the likely effective treatments (figure).

Ranking Results with Machine-Learning

Finally, Healx predicted which drug compounds known to treat diseases similar to fragile X are expected to be most effective in fragile X using a machine-learning algorithm (PRISM). Again using the case of the bread dough, if you have experience as a baker and know that previous attempts to improve batches of rye and white bread mix with disproportionate salt and yeast have benefited from the addition of compounds A, B or C, these are worth trying in wheat dough.

Tuning the List by Expert Review

Lastly, the repurposing experts at Healx considered the predictions of DGEM and PRISM in the context of scientific literature, clinical trials, drug and disease data, mining the data extensively both manually and using machine algorithms. They specifically looked for references to fragile X syndrome, and ultimately produced a ranked list of eight strong drug candidates for validation.

Next Steps: Drug Validation through the FRAX-DVI and Clinical Testing

While the repurposed drugs have been approved for general safety and the clinical predictions are promising, the results require validation. This is where the FRAX-DVI comes into play. Since 2012, Patricia Cogram, PhD of the University of Chile and Paulina Carullo, MD of the FLENI Foundation in Argentina have worked with animal models to validate new pharmaceutical leads for the treatment of fragile X. Dr. Cogram maintains colonies of fragile X mice and fruit flies, conducts standardized tests on lead therapeutic compounds, and compares their effects in the animals to previously tested drugs.

Because FRAXA has the established capability to test drugs in animal models quickly and cost-effectively, it should be possible to determine which drugs are the best candidates for clinical trials, and to move forward with those trials within the next year or two. This preclinical validation will also allow for testing of combinations of available drugs, which are potentially more effective than any single medication. Additionally, further repurposing studies could be useful, especially if additional human expression profiles can be obtained from different patient groups (i.e. other races, ethnicities, or countries). As repurposing technologies advance, we may also be able to expand the search to natural products and nutraceuticals, greatly increasing the range of potential available treatments.

Download Healx Fragile X Drug Repurposing Summary Report

For more information please contact Michael Tranfaglia, MD, FRAXA Medical Director.

THE AUTHOR
J. Dora Levin, PhD

J. Dora Levin, PhD is a science writer who is passionate about explaining complex scientific ideas and making them accessible to non-scientists. When speaking about this writing opportunity she said “I am truly excited about volunteering for FRAXA, an organization that consciously streamlines research and clinical trials through strategic planning and creative resourcing.”

Metformin, Diabetes Drug, Potential Fragile X Treatment

Metformin, Diabetes Drug, Potential Fragile X Treatment

McGill University Professor Nahum Sonenberg, PhD, sees promising results researching mice

Diabetes and fragile X syndrome may someday have something in common.

Diabetes is manageable and so could be fragile X syndrome.

Treatable.

And, yes, even curable — potentially.

All depends on the ability to create the right combination of medicines through painstaking, disciplined and comprehensive research efforts, says Nahum Sonenberg, PhD, James McGill Professor, Department of Biochemistry, McGill Cancer Center, McGill University.

Dr. Sonenberg is leading a team of researchers at McGill, in Montreal, Canada, which conducts research on the mechanism and control of translation (protein synthesis) initiation in eukaryotes (organisms whose cells contain a nucleus). Their goals are to understand the dysregulation of translation in those with fragile X syndrome, cancer, autism, neurodegenerative disease, and virus infections.

“If we understand this, we can devise drugs to cure many diseases,” said Dr. Sonenberg, who earned a PhD in biochemistry at the Weizmann Institute of Science, Israel. “In 20-30 years, we could change the outcome of many diseases.”

Regulating Protein Synthesis is Key

Key to fragile X research success will be regulating the amount of specific proteins in cells.

“All organisms need to make an exact amount of protein in each of our cells to live and survive,” Dr. Sonenberg said. “We cannot make too much or too little. In children with fragile X, MMP9 is a protein that is elevated. If we can inhibit this process, we will get less MMP9, normalize the brain and cure fragile X.”

If all goes well in human trials, Dr. Sonenberg expects treatment in patients with fragile X will go as well as for those taking diabetes medicine today. Likely benefits will be improved behavior, social interaction, sleep and cognition, and less hyper excitability.

“This will be a tremendous achievement,” he said. “So promising.”

Eliminating Side Effects for Clinical Trials

One of the biggest obstacles to human clinical trials is limiting or eliminating side effects of drugs used.

“Ideally, we are looking for a medicine that would not have any,” Dr. Sonenberg said. “Metformin is an oral diabetes medicine that helps control blood sugar levels and is the most prescribed drug for diabetes. It reduces the amount of MMP9. We treated mice with metformin and corrected all the core fragile X deficits. We are optimistic about using metformin in human clinical trials. This is a generic drug with few side effects.”

Fragile X Research is Rewarding

Dr. Sonenberg says FRAXA is an amazing organization because it simplifies the process of asking for grant money and organizes fragile X research conferences that are invaluable in advancing progress.

He wishes more organizations were like FRAXA.

“If they were, fragile X would have already been cured,” he said. “FRAXA has given us tremendous monetary support. I wish all grant writing was this easy. You cannot do better.”

Dr. Sonenberg was awarded the Robert L. Noble Prize from the National Cancer Institute of Canada in 2002, the Killam Prize for Health Sciences in 2005, the Katharine Berkan Judd Award from Memorial Sloan Kettering Cancer Center in 2007, the Roche Diagnostics Award in 2007, the Gairdner International Award in 2008, the CIHR Health Researcher of the Year Award in biomedical and clinical research in 2009, the Centenary Award of the Biochemical Society (UK) in 2011, the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science in 2012, and the Wolf Prize in Medicine in 2014.

He says research on fragile X syndrome has been very rewarding.

“It makes me happier to do something to cure people of this devastating disease,” he said. “It gives a sense of purpose. It’s more important to make life better for others with this disease.”

Nahum Sonenberg

FRAXA Funding for the Sonenberg Lab

FRAXA Research Foundation has awarded:

Fragile X Nervous (System) Breakdown

Researcher explores neurons and the nervous system to reduce the effects of fragile X syndrome

"The occurrence and development of events by chance in a happy or beneficial way"

That’s how Lynne E. Maquat, PhD, describes the process of how her research extended to fragile X syndrome to better understand it and ultimately find advanced treatments.

“As a card-carrying biochemist/molecular biologist, most of my 35-plus year career has been spent discovering the causes of inherited human diseases,” said Dr. Maquat, J. Lowell Orbison Endowed Chair and Professor, Department of Biochemistry and Biophysics, School of Medicine and Dentistry, and Director, University of Rochester Center for RNA Biology. “While studying one disease and simultaneously obtaining results pertinent to fragile X syndrome, together with knowing there is no cure for fragile X syndrome, my lab jumped at the chance to make a difference.”

Breaking Down Neurons

In fragile X syndrome, neurons don’t mature properly.

This leads to the failure of the nervous system to effectively transmit information. Reasons remain unclear, but one laboratory has solid evidence the stability of many messenger RNAs — the molecules that produce proteins in our cells — is abnormal.

“We believe these abnormalities contribute to the development of fragile X.”

Controlling NMD Is Key in Fragile X

Nonsense-mediated decay (NMD) plays an important role in fragile X, as well as many other genetic syndromes. NMD is a “housekeeping” process that protects cells from mistakes they often make when expressing genetic material. It is used by cells to help them adapt when growth conditions change.

“We’ve found NMD is hyper-activated in fragile X syndrome,” said Dr. Maquat, who earned a BA in Biology at the University of Connecticut and a PhD in Biochemistry at the University of Wisconsin-Madison. “NMD is working overtime, and this extra activity could be detrimental to cells in the brain.”

Can Approved Drugs Help?

The good news is there are approved drugs on the market that inhibit NMD.

But in order to match an appropriate drug with the needs of fragile X patients, researchers need to understand the specific molecular defects that lead to fragile X.

“Drugs target molecules in our cells, so once we know the molecular cause of fragile X and how exactly NMD plays a role we can pick or develop a drug that targets that particular process,” Dr. Maquat said.

The goal is to identify drugs that are likely to be more effective and have fewer side effects because they target a particular mechanism. Although her lab has not yet tested approved drugs on patients with fragile X, researchers have used human kidney cells, which are easier to work with than neurons, to recapitulate fragile X syndrome and understand how NMD is in over-drive.

“This is one approach to precision medicine, and we want to use this approach to tackle fragile X,” she said. “I believe we are the only lab studying fragile X from the molecular perspective of NMD and messenger RNA stability. Moving forward, we plan to use skin cells from fragile X patients and brains cells from individuals without the disease that we can engineer to behave like neurons from fragile X patients.”

FRAXA Support Is Critical for Fragile X Research

Dr. Maquat said her biggest obstacles are financial.

It is very expensive to develop the proper cells to study fragile X syndrome and her lab could not have gotten as far without funding.

“We are extremely grateful to the FRAXA Research Foundation,” Maquat said. “FRAXA’s support has been essential to our work. Without FRAXA funding, my lab would not be pursuing research on fragile X, which is desperately needed. Though the work in my lab is considered basic science, our ultimate goal is to help people. It’s only through funding from FRAXA and other organizations that we can bring new treatments to patients who need them."

 

Did tolerance result in Fragile X mGluR5 clinical trial failures?

Did tolerance result in Fragile X mGluR5 clinical trial failures?

Remember the Novartis and Roche large-scale clinical trials that failed a few years ago?

Who could forget?

Certainly not Rebecca Senter, PhD, FRAXA postdoctoral fellow, Massachusetts Institute of Technology.

Although the 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, Picower Professor of Neuroscience, Department of Brain and Cognitive Sciences, MIT, to carefully review parent observations during the trials. Those caregiver reports suggested tolerance to metabotropic glutamate receptor 5 (mGluR5) antagonists developed quickly, consistent with some preclinical findings in the mouse model.

Recognizing the importance of these findings, FRAXA last year funded a two-year MIT project to explore if mGluR5 antagonists dosed chronically causes tolerance, and if so, how it develops and to probe new avenues to prevent or circumvent it.

During the first year, Dr. Senter and Dr. Bear showed there is indeed tolerance after just three doses of an mGluR5 antagonist in mice that have been bred to mimic fragile X syndrome. They are now investigating how and why the tolerance occurs and — most importantly — how to combat it.

Impacting Future Fragile X Clinical Trials

Dr. Senter’s research goal is to understand how and why tolerance develops to chronic dosing with mGluR5 antagonists in fragile X patients.

"We can design the best therapy possible, but if it can’t be dosed chronically in patients, then it isn’t going to work for fragile X," said Dr. Senter, who is moving to a position at a pharmaceutical company. "Fragile X is a lifelong disorder, and thus it is worthwhile to understand why this tolerance is developing. Is it specific to the mGlu5 mechanism? Is it specific to fragile X?"

"Because there is so much hope in the field for mGluR5 antagonists as a viable therapeutic mechanism to treat fragile X, it’s worthwhile to understand what’s going on mechanistically to understand why this tolerance develops with the hope of being able to take our findings into consideration when designing future clinical trials. Not only will our results provide a possible mechanism for why tolerance develops to chronic mGluR5 antagonism and how to circumvent it, it may also provide insight into other therapeutic mechanisms in the future."

Understanding Tolerance

Tolerance is an enormous problem in many drugs, and particularly in drugs that impact the brain. Through the FRAXA-funded study, the MIT researchers have learned several interesting things about tolerance.

"First, we’ve been able to observe tolerance reliably in the mouse model of fragile X," Dr. Senter said. "This finding is important because it builds upon the parent reports from the clinical trials and previous external research. The second observation is the tolerance pathway is due to alterations in the signaling from mGluR5 to protein synthesis, which has been well characterized by several labs in the field. Because of this, we are excited and hopeful to be able to understand what is happening in the mouse model with the goal of being able to figure out if there are ways to circumvent the development of tolerance."

FRAXA Is ‘Amazing’

Dr. Senter said her work on this project would not have been possible without the support of FRAXA.

"FRAXA’s commitment to funding research that directly addresses the difficult questions in the field is amazing," she said. "I was interested in working on fragile X because we understand so much about the underlying biology, yet we have not been successful in finding a therapeutic intervention that lasts in patients. Investigating tolerance dovetails nicely with my training from graduate school and allows me to continue working in the field of neurodevelopmental disorders."

 

Mark Bear's goal: disease-modifying treatments for fragile X

 

FRAXA Grants to Robert Bauchwitz, MD, PhD — Columbia University

 

Repurposing Available Drugs to Treat Fragile X Syndrome – FRAXA Initiatives

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 the fragile X mouse model. This key result launched all the further studies.

1999: Darnell (Rockefeller) and Broadie (Vanderbilt) labs independently found that FMRP regulates MAP1b translation and GSK3 activity, suggesting lithium as a potential therapeutic. Lithium is an available drug which inhibits both GSK3 and MAP1b. FRAXA then funded the Bauchwitz lab at Columbia and the Jope lab at UAB to validate lithium and investigational GSK3 inhibitors in fragile X animal models. FRAXA then funded a pilot clinical trial of lithium (Berry-Kravis atRush U.) with good results; larger follow-up studies are still needed (NIH declined to fund these).

Baclofen

1998: The Toth lab (Cornell-Weill) described sensory hypersensitivity in fragile X mice which can be treated with baclofen. FRAXA then partnered with Seaside Therapeutics for clinical trials of arbaclofen, a proprietary version of the available drug. Seaside went out of business, but many patients with fragile X continue on baclofen today.

Minocycline

2007: The Ethell lab (UCR) found excessive activity of matrix metalloproteinases (MMP-9) in fragile X, resulting in impaired synaptic maturation. The available drug minocycline, a known MMP-9 inhibitor, was shown to rescue this deficit. FRAXA organized and funded a clinical trial of minocycline, demonstrating excellent clinical response. Many fragile X patients currently take minocycline. FRAXA went on to partner with Paratek to investigate other agents which can inhibit MMP-9 without antibiotic activity. Another clinical trial of minocycline by Dr. Randi Hagerman in 2013 also showed good results.

Lovastatin

2010: The Bear lab (MIT) showed that the available drug lovastatin can reduce mGluR signaling and reverse signs of fragile X in animal models. FRAXA funded clinical trials of lovastatin in Quebec, with promising results. FRAXA is currently funding a follow-up combined study of lovastatin and minocycline in patients with fragile X.

Green Tea Extract

2012: FRAXA funded preclinical studies in Fragile X mice and a double blind, randomized clinical trial in Fragile X patients using Mega Green Tea Extract in the Barcelona, Spain lab of Dr. Mara Dierssen. Dr. Dierssen has submitted a paper reporting results of this study, and we are awaiting results.

Metformin

2014: After multiple investigators (Vanderklish at Scripps, Sonenberg at McGill, Jongens and McBride at UPenn) discovered potential therapeutic effects of metformin in fragile X animal models, FRAXA funded a study to validate metformin in live animal model at FRAX-DVI (see below).

Our Global Repurposing Strategy

Because repurposing available drugs is so much faster and more cost-effective than advancing investigational drugs, we’ve launched additional projects with wide-ranging potential.

In 2012, FRAXA established the Drug Validation Initiative (FRAX-DVI) in South America to conduct rapid validation of candidate drugs in fragile X animal models. This has led to more than 30 currently active partnerships with pharmaceutical companies. FRAX-DVI also allows for validation of available drugs emerging from studies by other labs without in vivo capability.

FRAXA is partnering with Healx (Cambridge, UK) to conduct repurposing studies based on transcriptional profiling. This project is expected to produce a ranked list of potentially useful drugs which we plan to further test at FRAX-DVI. We are organizing clinical trials of the most promising available drugs – notably metformin – to assess these drugs and to gain a better understanding of biomarkers, outcome measures, and overall clinical trial design for fragile X, autism, and related developmental disorders.

While there is still a lot more work to do before any of these strategies can be considered proven therapies for fragile X, we are excited about the possibilities of repurposing existing drugs for fragile X. We eagerly look forward to the results of these and future studies!

Fragile X Research Tackles High Anxiety – Peter Vanderklish

Scripps Research Institute Researcher Peter Vanderklish Tackles High Anxiety in Fragile X Syndrome

Fragile X Research Tackles High Anxiety in Fragile X

It’s often said love makes the world go ’round.

For families of children with fragile X, their worlds often evolve around anxiety.

Yes, we all know the signs of fragile X anxiety: Ears begin turning red followed by incessant pacing, heavy breathing, stiffening body, flapping, jumping, avoidance or yelling. Sometimes, it’s the more severe screaming, pinching, scratching, biting and general tearing things up or, worse, the nuclear meltdown.

Peter Vanderklish, PhD, associate professor, Cell and Molecular Biology, The Scripps Research Institute, knows the signs all too well. He believes anxiety is among the most highly debilitating aspects of fragile X.

Thanks to a grant from FRAXA, Vanderklish is studying why people with fragile X suffer from such severe, persistent and largely intractable anxiety. His goal is to translate what he finds into therapies tailored to fragile X by targeting anxiety as a core symptom. An additional goal is to treat other emotional symptoms stemming from anxiety, including reducing social aversion and improving cognition. There is also the possibility that alleviating anxiety may lead to cognitive improvement.

Neural Origins of Anxiety

Dr. Vanderklish and his collaborator at Scripps, Dr. Walter Francesconi, have been taking a new look at the neural origins of anxiety in fragile X. “One of the most exciting aspects of our current work is the synaptic and neural changes we see in the BNST (bed nucleus of the stria terminalis) of fmr1 knockout mice, which in principle should predispose to chronic anxiety” said Vanderklish, who has been awarded $415,000 in FRAXA funding since 2004. “This maps quite nicely to recent work we conducted, which showed high local changes in enzymes in these pathways. So, our new data and hypotheses — which were derived from a systems neurobiology view of chronic anxiety — find support in the results of a large, unbiased molecular screen for synaptic protein changes in fragile X.”

Improving Daily Life

Vanderklish believes his biggest potential research benefit will be to improve the day-to-day quality of life for those with fragile X and their families by reducing social anxiety.

“We all know how disruptive even transient anxiety can be,” said Vanderklish, who earned a PhD. in Neurobiology, University of California, Irvine, in 1997. “So, when you consider anxiety in fragile X is multiform, chronic, intense and largely intractable, you realize it must be a huge disruption to their well-being.”

Parent surveys confirm this, Vanderklish said.

“Many rank anxiety as the most disruptive and costly symptom of fragile X,” he said. “We are currently trying to improve a social anxiety paradigm in mice to provide a better test of the anxiolytic effects of drugs that correct synaptic and neural imbalances in the BNST.”

Fragile X: A Rapidly Evolving Field

Vanderklish said he is “very grateful” to FRAXA for supporting his project.

“Working on fragile X impacts me in several ways,” he said. “On a scientific level, I have the opportunity to be part of a field that draws from all areas of neuroscience -- one that is evolved in a rapid and meaningful way by a committed group of parents, scientists, clinicians and others. There’s a real chance here to translate basic research into effective mechanism-based therapies. I find the devotion and commitment shown by FRAXA to be inspirational.”

Vanderklish remains optimistic that viable therapies for fragile X will emerge from the current set of approaches being advanced by the field.

“Recent efforts that focus more specifically on core symptoms of fragile X,” he said, “such as sensory hypersensitivity and anxiety, may play a role in so many other symptoms, even cognitive impairment, and will be particularly fruitful.”

University of Cambridge startup Healx is Rapidly Identifying Existing Drugs to Help Fragile X Patients

Healx scientists use drug repurposing to rapidly identify existing drugs to help Fragile X patients
Narissa Gipp, Head of Patient Engagement; David Cavalla, Chief Scientific Officer; and Dan Mason, Molecular Informatics Data Scientist; at Healx
Her Majesty Queen Elizabeth II congratulates Healx CEO Tim Guilliams. Healx is using drug repurposing to rapidly identify existing drugs to help Fragile X patients. Healx was awarded 2016 ‘Cambridge Graduate Business of the Year.’

Why Reinvent the Wheel?

Drug Repurposing is considerably faster and cheaper than normal drug discovery.

With a $44,000 grant from FRAXA, awarded in September, 2016, University of Cambridge (England) startup Healx is taking this approach to identify novel therapies based on existing drugs to help those with fragile X syndrome.

“We use genomic information to help identify which drug will be best suited to counteract the effects of the fragile X condition,” said Narissa Gipp, Head of Patient Engagement, Healx. “Literature mining techniques are used to search through the entire scientific literature to identify additional information that can help match existing drugs to rare diseases.”

Sophisticated drug-matching technologies, which originate from the University of Cambridge, are used to identify hidden links between existing drugs and rare diseases. The most promising drugs are then tested experimentally in fragile X models. In case an approved drug is indeed safe, a pivotal clinical trial can be developed in a small group of patients to assess efficacy.

Given a successful result, doctors could then consider “off-label” prescription of the medicine to improve quality of life for fragile X patients, while the final stages of clinical development are being conducted.

“Overall, drug repurposing is a quick and cheap way of delivering potential treatments,” Gipp said.

Healx’s three-phase analysis process includes dataset searches, incorporating gene expression quality checks, and candidate compound list derivation.

“Application of novel drug-matching technologies can significantly help accelerate this process,” Gipp said. “The generation of excellent gene expression data is important. It helps understand the effects in detail and therefore increase the likelihood of performing successful drug-matching.”

Gipp said working with FRAXA is “fantastic.”

“FRAXA is incredibly well organized and established,” she said. “Its program of research and drug discovery can very effectively help progress successful drug candidates to the next stages of development. The resulting findings will also greatly help progress other rare diseases, such as Pitt Hopkins syndrome among others.

“We are incredibly excited about working together with FRAXA to help identify new effective treatments.”

Attention, Scientists: Request for Transcriptomic Data

FRAXA awarded $44,000 to Healx for the project, Identifying Novel Therapies based on Existing Drugs for Fragile X Syndrome.  This drug repurposing project aims to use advanced data analytics and machine learning to predict which approved drugs could have a therapeutic effect on Fragile X patients. As part of this study the investigators are using transcriptomic data to facilitate the drug/disease matching process. Data has been obtained through open sources, however the more data we can add to this study the greater likelihood we have of identifying a new potential treatment.

In particular we are looking for transcriptomic data and good case controls in the condition. If you have data available and are interested in joining this project don’t hesitate to get in touch.

This additional data will help us to identify potential drugs which can be repurposed for the treatment of Fragile X Syndrome.

Narissa Gipp
Head of Patient Engagement
Healx
narissa@healx.io

More Research News

Trial and No Error: Better Outcomes for Clinical Trials in Fragile X Syndrome

Christina Timmerman - Meffert lab

Johns Hopkins researcher Christina Timmerman, PhD, searches for a less subjective method to determine if a drug is working in patients with fragile X syndrome

Many parents of children with fragile X syndrome were crushed when promising drug trials were unexpectedly stopped a few years ago because subjective behavior-based outcome measures did not justify continuing the trials.

The strong feelings linger today.

If all goes well with Christina Timmerman’s research, future drug trials may be able to continue with additional metrics for assessment, until there are advanced treatments or even a cure for Fragile X syndrome.

This will be welcome news to parents.

Timothy Gamache, graduate student, and Christina Timmerman, PhD
Timothy Gamache, graduate student, and Christina Timmerman, PhD

“We hope a more quantitative outcome measure, such as the proposed microRNA biomarker, would allow for a less subjective method to determine if a drug is working or not,” said Dr. Timmerman, Postdoctoral Fellow, Lab of Mollie Meffert, Department of Biological Chemistry, Johns Hopkins School of Medicine. “Our research is aimed at discovering a potential microRNA blood-based biomarker that can be used as a clinical outcome measure for fragile X syndrome.”

Objective, not subjective

Currently, all fragile X drug trials are behavior based and highly subjective. The ultimate goal of a fragile X syndrome biomarker would be to provide an objective measure of drug treatments and other therapeutic interventions.

“With the discovery of a fragile X syndrome biomarker, our hope is that this would have the potential to help identify whether a drug was having a therapeutic effect on a fragile X syndrome patient,” she said. “While studying the basic biology behind fragile X syndrome in mouse models, we noticed the biochemical pathways we found to be dysregulated in the brain were also being dysregulated outside of the nervous system, specifically in the blood. We also knew microRNAs isolated from cell-free fractions, such as plasma and serum, are thought to be highly stable, which makes them attractive targets as biomarkers.”

So, a simple blood test could be used to evaluate potential new treatments for fragile X.

Let’s collaborate

Dr. Timmerman credits FRAXA funding with helping her connect her basic research to top-notch clinical research worldwide.

“FRAXA has helped us set up promising collaborations with clinicians, such as Dr. Elizabeth Berry Kravis and Dr. Francois Corbin, who work directly with patients with fragile X syndrome, and this gives us an exciting chance to validate our biomarker in patients,” she said. “While investigating mechanisms of gene expression, particularly post-transcriptional mechanisms such as those that work through microRNAs, we choose to extend our studies into a disease model. Based on our previous work, we hypothesized that our basic molecular mechanistic characterizations the brain would allow us insight to a disease state such as fragile X syndrome.”

Dr. Timmerman believes working in the fragile X field has given her a deeper appreciation for the capacity of basic research to help patients and the families of those afflicted with fragile X syndrome.

“It has guided our work into the biomarker project, as we hope this work might truly benefit patients with fragile X in the future,” she said.

 

Mollie Meffert, MD, PhD Principal Investigator Johns Hopkins Univ.

MicroRNAs as Biomarkers in FXS

FRAXA Postdoctoral Fellowship
awarded to Christina Timmerman, PhD
with Mollie Meffert, PhD, Principal Investigator
Johns Hopkins University
Funded in May 2015
$90,000 over 2 years

The search for blood-based biomarkers in fragile X has been a topic of intense interest in recent years, and is seen by many in the field as essential to the development of new treatments. While most of the effort has focused on measuring proteins which are increased or decreased in fragile X, this project takes a very different approach. Dr. Mollie Meffert, Dr. Christina Timmerman, and colleagues are looking at groups of small RNAs, known as microRNAs, which are greatly decreased in the brains fragile X mice vs. normal mice. MicroRNAs are also easily measurable in blood, making them attractive as candidate biomarkers.

NIH investigator Carolyn Beebe Smith, PhD, looks to improve sleep in Fragile X Syndrome

sleep in fragile X syndrome - can it be improved?
FRAXA postdoctoral fellow, Rachel Sare, PhD, and Carolyn Beebe Smith, PhD

Our sons with Fragile X Syndrome typically go to bed early and rise early.
Sometimes they jump on us while we are sleeping at 3 a.m., excited to start their day.

For heaven’s sake, whY, wHY, WHY?

The answer may come from Carolyn Beebe Smith, PhD, senior investigator, Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. She is studying why children, in particularly boys, with FXS have problems sleeping.

“We know sleep is important for many aspects of brain function,” said Dr. Smith, who received a PhD from the University of London where she studied the chemical pathology of Alzheimer’s for which she was awarded the Queen Square Prize. “In studies of healthy mice, we have shown restricted sleep during brain development can result in long-lasting changes in behavior. We are interested in understanding if sleep problems contribute to severity of symptoms in boys with FXS. Improving sleep is a simple and realistic therapeutic target.”

Better sleep, better for everyone!

Dr. Smith aims to understand if sleep is altered in the mouse model of fragile X syndrome.  If it is, then she plans to use medications to correct sleep, determine if remedying sleep can lead to improvements in behavior, and target sleep, in combination with other therapeutics, to yield better outcomes in the mouse model. Her research focus is on two major issues:
1. Autism spectrum disorders in which a dysregulation of cerebral protein synthesis may underlie abnormal phenotypes and
2. The role of protein synthesis in sleep and memory consolidation.

Her study is a preclinical trial of FDA-approved drugs. If her research results in improved performance in the mice, trials in patients would be the next step.

“This research into a novel yet relatively simple therapy has the potential for improving the behavioral outcome in patients with FXS,” she said. “Previous work in my lab has focused on dysregulated protein synthesis in the mouse model of FXS. We have used rates of protein synthesis and behaviors, such as open field behavior, social behavior and anxiety-related behaviors, as outcome measures to show efficacy of chronic treatments with lithium and R-baclofen.”

Dr. Smith is also studying young men with FXS to see if measurements in mice hold true in humans. “Findings of circadian rhythm abnormalities in mouse and fly models of FXS led us to ask about possible effects of sleep deficits,” she said.

‘Tremendously satisfying experience’

Dr. Smith chose researching FXS as a continuation of her lab work in studying cerebral protein synthesis and its role in adaptive responses in the nervous system for several decades.

“In FXS, the protein that is missing (FMRP) is a regulator of translation,” she said. “It was of great interest to us to study the effects of the absence of FMRP on translation in the mouse model and also in human subjects. Rates of translation in nervous tissue may be a potential marker of the disease and treatment efficacy.

“As a basic scientist, this has been a tremendously satisfying experience. For me, the study of FXS has led me to translate our findings in the mouse model to a study of human subjects and the experience of running a clinical study.”

FRAXA is ‘extraordinary’

Dr. Smith credits FRAXA funding support for making her research possible.

“FRAXA does an extraordinary job of promoting a collegial atmosphere for investigators in this field and recruiting young investigators to the field through these fellowships,” she said. “We are really grateful to FRAXA for the funding and think FRAXA does a tremendous job for both researchers and patients.”


About the Author

Ted Coutilish author Ted Coutilish and his son, Andrew

Theodore G. Coutilish is celebrating his 10th year as Associate Vice President of Marketing at Eastern Michigan University, Ypsilanti, Michigan. Coutilish has enjoyed more than two decades of higher education marketing communications leadership experience. Since 2011, he has successfully led the university’s TRUEMU marketing campaign, leading to record new student enrollment.

Over the years, his peers have recognized his work with numerous prestigious awards, including IABC Detroit’s 2012 Communicator of the Year, the chapter’s highest honor, recognizing lifelong professional communications excellence. In addition, he and his wife, Mary Beth Langan, were recognized with the 2012 Halstead-Bresnahan Family Award at the 13th Annual International Fragile X Conference, Miami, Florida, recognizing those who make a profound difference to families affected by fragile X syndrome. Coutilish was named “Distinguished Alumni in 2013” by Grosse Pointe North High School, the school’s highest honor, recognizing professional and community achievements. He lives in the City of Grosse Pointe, Michigan, with his wife, and their son, Andrew, who has Autism and Fragile X Syndrome. He earned a MA in liberal studies with a concentration in communications from University of Detroit Mercy in 1994 and a BA in print journalism in 1987 from Wayne State University.

New Fragile X Clinical Trial for Children launching in June 2017

Rush University Medical Center Professor Elizabeth M. Berry-Kravis, MD, PhD, begins a large-scale clinical trial to study effects of AFQ056, an mGluR5 blocker, on learning in young children

BERRY tenacious!Elizabeth Berry-Kravis, MD, PhD, starting new fragile X clinical trial

You can say a lot about Elizabeth M. Berry-Kravis, MD, PhD:

• University of Notre Dame and University of Chicago educated.
• Professor of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center.
• Board certified in neurology with a special qualification in child neurology.
• Expert in Fragile X syndrome and other neurogenetic diseases.

You can also say she’ll talk your ears off. Literally! And much of it may go over your head. Yes, she often talks in industry jargon. Plenty of it. OK, we get it. She’s smart. Super smart. She’s caring. Super caring. She’s knowledgeable. Super knowledgeable. But did you know she’s tenacious? Incredibly, super-duper, berry tenacious?

Good thing for us she’s on our side.

No doubt her newest research efforts will prove all of these qualities and more, especially the incredibly, super-duper, berry tenacious part.

Starting in June 2017, she will begin a large-scale clinical trial of Novartis AFQ056 (an mGluR5 antagonist) with children to change the way drugs are developed for fragile X and developmental disabilities in general. Funded by the National Institutes of Health through the NeuroNext network, Berry-Kravis wants to show effects of a targeted treatment — the mGluR5 blocker for fragile X that failed in previous adult trials and works on brain plasticity in fragile X mice — can be better evaluated by studying effects on learning in young children.

“We will see if language learning in 3 to 6 year-olds with Fragile X Syndrome can be accelerated by the drug,” Berry-Kravis said.

If all goes well with her research, Berry-Kravis would build off learning from previous failures and successes in FRAXA- and industry-funded clinical trials to better understand how to avoid repeating the failures of previous promising new drug treatments tested in adults.

“The trial will be very complex and challenging to carry out and will need everything to be done according to exact protocols,” said Berry-Kravis, who is on the FRAXA Research Foundation Advisory Board. “Accelerating drug development for targeted treatment of FXS with new types of trial designs is our biggest challenge right now.”

Berry-Kravis, who established the comprehensive Fragile X Clinic and Research Program at Rush in 1992, provides care and support to more than 600 patients with fragile X syndrome for management of neurological, medical, behavioral and genetic issues. She says FRAXA support got her started in the development of trial designs for treatment trials in FXS.

“I happened to work on FXS when working on another project and it has been a model of what I wanted to do in my life, which is find ways to understand how brain cells connect and communicate with each other, and to fix disorders where this process is not working as well as it should,” said Berry-Kravis, who won the American Academy of Neurology Sidney Carter Award and the John Merck Fund Spark Plug Award, both in 2016 for her work in fragile X syndrome. “I have met so many wonderful families through FRAXA and my work in fragile X. I have enjoyed working with these families and my patients and I have been able to spend my career working on exactly what I wanted to study from the time I was 12 years old.”

https://www.rushu.rush.edu/news/going-distance-children


About the Author
Ted Coutilish author
Ted Coutilish and his son, Andrew

Theodore G. Coutilish is celebrating his 10th year as Associate Vice President of Marketing at Eastern Michigan University, Ypsilanti, Michigan. Coutilish has enjoyed more than two decades of higher education marketing communications leadership experience. Since 2011, he has successfully led the university’s TRUEMU marketing campaign, leading to record new student enrollment.

Over the years, his peers have recognized his work with numerous prestigious awards, including IABC Detroit’s 2012 Communicator of the Year, the chapter’s highest honor, recognizing lifelong professional communications excellence. In addition, he and his wife, Mary Beth Langan, were recognized with the 2012 Halstead-Bresnahan Family Award at the 13th Annual International Fragile X Conference, Miami, Florida, recognizing those who make a profound difference to families affected by fragile X syndrome. Coutilish was named “Distinguished Alumni in 2013” by Grosse Pointe North High School, the school’s highest honor, recognizing professional and community achievements. He lives in the City of Grosse Pointe, Michigan, with his wife, and their son, Andrew, who has Autism and Fragile X Syndrome. He earned a MA in liberal studies with a concentration in communications from University of Detroit Mercy in 1994 and a BA in print journalism in 1987 from Wayne State University.