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

Fragile X Awareness Day Origins and a Tribute

July 22 is National Fragile X Awareness Day, but I’ll bet few know the history behind it.

In 2000, before there was such a thing as a Fragile X Advocacy Day, FRAXA Research Foundation and David Busby (husband to Mary Beth, father to two adult sons living with fragile X, a member of FRAXA’s pioneering leadership team, and a prominent and politically well-connected DC lawyer) were running fragile X advocacy in Washington, DC.

Today’s Senate Champions are Sen. Stabenow and Isakson. But in the late 90’s it was David and FRAXA who were running things and David secured commitments from the first Senate Champions, John Edwards and Chuck Hagel. And, it was David and a small group of FRAXA advocates who went to DC and convinced those initial champions to introduce “The Fragile X Research Act” in 1998.

The bill never passed as Congress was unwilling to pass a research bill for a single condition. But David and his group went back to the drawing board, helped form and teamed up with a new coalition known as the “Coalition for Children’s Health” and went to work on a new bill which came to be known as the “Children’s Health Act of 2000”.

The Children’s Health Act of 2000

The Children’s Heath Act of 2000 was essentially the same as the “Fragile X Research Act” but it brought together other loosely knit groups that were also knocking on the door to get their own “Research Acts” passed (Autism, Juvenile Arthritis, Juvenile Diabetes and Childhood Asthma). Since Congress said no to a research bill for only one condition, the “Children’s Health Coalition” was formed to accomplish the same thing, but as a group, which would propose a bill covering multiple conditions.

David reached out to me and invited me to join the Coalition. I made my first-ever trip to Washington, DC to meet with David and the Coalition and I was hooked. David took me under his wing, introduced me around and taught me the ropes. I think David was semi-retired even then and he was excited at the prospect of having someone to take over the reins of fragile X research advocacy. For me, it was like entering a Masters level program with David as my professor.

Regular trips to DC followed and the Children’s Health Act of 2000 passed. The “Red Line” copy with the “wet” signatures of Denny Hastert, Strom Thurmond, and Bill Clinton is below. This framed copy was a gift from Professor Busby with David’s personal letter of thanks. They hang in my office with my other diplomas.

The First National Fragile X Awareness Day

David also introduced me to my next professor. A prominent DC consulting firm, then known as Baker Daniels, had allowed one of it’s bright, young, just off the Hill consultants, to work pro-bono as the Chair of the Coalition for Children’s Health. That fire-brand provided hundreds of hours of tier-one consulting, organization, motivation and expertise which were instrumental in passing the CHA of 2000.

Many of you probably know her. Her name is Serena Lowe. Working closely with David and Serena opened my eyes to a world of possibilities for FX and laid the foundation for the fragile  X community’s effective advocacy efforts ever since.

As for National Fragile X Awareness Day, David Busby’s work resulted in much goodwill with many powerful members of Congress. FRAXA was then, and remains now, focused on research aimed at finding effective treatments and ultimately a cure for fragile X. But they knew the importance of awareness too, and so David asked for a favor, and a Congressional designation of a National Fragile Awareness Day followed. The proclamation was presented to the National Fragile X Foundation as a surprise gift! I’ll bet you didn’t know that, so, thanks David and thanks FRAXA.

I’ll bet you also didn’t know that my friend, mentor, and FRAXA pioneer, passed away at the end of last year at the ripe old age of 90. I only found out recently myself and feel fortunate to be able to re-tell this story as a way of paying tribute to my friend on Fragile X Awareness Day.

Thank you, David, for your friendship, for imparting your knowledge, and for partnering with Katie and Mike on their journey. I’m sorry you didn’t live to see the cure but because of the mountains of good you did for fragile X we’ll get there, no doubt. Your legacy lives on, my friend.

Children's Health Act of 2000
Children's Health Act of 2000

Jeffrey Cohen is the father of 28-year-old fraternal twins who are living and thriving with fragile X syndrome. He has lectured extensively about fragile X and has been a regular presenter at FX conferences. For nearly 25 years he served in a variety of volunteer and staff positions with the NFXF including board president, director of government affairs and interim executive director. In 2002 he received the Foundation’s Spirit of Excellence Award, in 2003, the Maxwell J. Schleifer Distinguished Service Award from Exceptional Parent Magazine and in 2010, the Foundation’s Lifetime Achievement Award. He received his Bachelor’s Degree in Business Administration in 1980 and his Juris Doctorate in Law in 1983, from Wayne State University in Detroit, MI. He currently lives with wife Arlene and adult children Josh and Alli in Carefree, Arizona and has returned to the full-time practice of law.

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.”

FRAXA Wins Award for Drug Repurposing

An Alternative Path to Finding Treatments

Cures Within Reach, the leading global nonprofit focused on repurposing research as a fast track to saving patient lives, has awarded FRAXA Research Foundation the 2017 Golan Christie Taglia Patient Impact Philanthropy Award for efforts to find treatments for the rare disease fragile X syndrome.

Dr. Michael Tranfaglia, FRAXA’s co-founder, accepted the award at the 5th Annual Global Health Repurposing Awards in Chicago. He also spoke at the companion 6th Annual Drug Repositioning, Repurposing and Rescue Conference.

“This award will continue to raise awareness of the key role repurposing treatments can play in treating disorders like fragile X and other rare diseases,” noted Dr. Tranfaglia.

Cures Within Reach - Repurposing Treatments

Drug Repurposing is Faster, Cheaper, Less Risky than Developing New Medicines

There are over 7,000 rare diseases worldwide that do not have effective treatments. But each year only 10-15 new drug treatments are developed.

Advancements in technology mean that interactions between known drugs and unsolved diseases can be rapidly modeled, tested and shared around the world. This presents a huge opportunity to help patients. FRAXA invests millions of dollars in pursuing drug repurposing and is exploring the potential of available medicines for fragile X, including metformin, minocycline, lithium, and others. Read more about our initiative Repurposing Available Drugs to Treat Fragile X Syndrome.

 

CureWithinReach - why repurposing treatments for fragile X

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:

Funding Opportunities for Fragile X Research 2017-18

Mahmoud A. Pouladi, PhD & Kagistia Utami, PhD of National University of Singapore and Agency for Science, Technology and Research (A*STAR)

2017-18 Priorities for FRAXA Research Grants

FRAXA has funded more than $26 million in medical research aimed at finding specific treatments and ultimately a cure for fragile X syndrome. FRAXA awards two categories of grants, and guidelines for these grants have changed significantly from previous years. The purpose of the changes is to place a greater emphasis on clinical trials, while still continuing to fund worthwhile translational research and other early-stage work.

Focus is on Clinical Trials

The previous category of “FRAXA Program Grants” has been eliminated, in part because these grants have not focused on clinical research to the desired extent. In its place, we are introducing FRAXA Clinical Trial Grants. These grants are strictly for clinical research with fragile X subjects. Strong emphasis will be placed on clinical trials of potentially disease-modifying agents which have been previously validated in fragile X animal models. Other types of clinical research may be considered, such as biomarker studies in fragile X patients, or trials of symptomatic therapies; however, these will be accorded lower priority in funding decisions. Budgets and grant structure are flexible but may be subject to some negotiation.

Letters of Intent are required for submission of Clinical Trial Grant applications. We are flexible about deadlines for submission, given the complexities of organizing clinical research.

Summary - Clinical Trial Grants

  • Flexible in amount and duration.
  • Must involve human subjects with fragile X.
  • Highest priority is given to clinical trials of potentially disease-modifying therapeutics which have previously been validated in fragile X animal models.
  • Applications may be submitted at any time, but a Letter of Intent (LOI) to Michael Tranfaglia, MD is essential.
Fragile X Researcher, Cara Westmark, PhD

FRAXA Fellowships

Our postdoctoral fellowships have been successful over the years, and we have decided to make this program more flexible. FRAXA Fellowships provide $45,000 per year for 2 years. Any scientist is eligible for salary support from these awards (not just postdocs), and a supply budget may be included. Given the flexible nature of the new fellowships, a detailed budget is required. Only one position will be supported per project, and the individual should be working at least ½ time on the project. In other words, we cannot consider requests for partial salary support for PI in addition to support for junior staff; however, we are willing to consider requests for PI salary support as the primary focus of the proposal.

These are significant changes from our previous Fellowships. It is recommended that potential applications send a brief Letter of Intent to Michael Tranfaglia, MD  well in advance of a formal application.

Summary - Fellowships

  • $45,000 per year.
  • Renewable for a second year of funding (maximum), assuming successful progress and timely submission of a renewal application.
  • Supply budget is allowed.
  • Any university-based lab in the world may apply; we do not give preference to any specific country.
  • Salary support for one scientist (any degree of BS or higher) working at least ½ time on the project.
  • Priority is given to research with a translational or preclinical focus on fragile X, which has potential to lead to improved treatment.

Background and Rationale

FRAXA Research Foundation continues to focus on research which is likely to lead to new and improved treatments for fragile X syndrome, with an emphasis on disease-modifying therapeutics based on understanding of fragile X disease mechanisms. Our goal has always been to accelerate the pace of research by eliminating “bottlenecks” in this long and complex process, and we have been quite successful in this regard. Since our funding priorities are determined by the state of the research and the nature of these bottlenecks, we constantly re-examine these priorities as the field progresses.

In the early years of FRAXA’s existence, little was known about basic disease mechanisms, so we placed great emphasis on funding of basic research to understand the pathophysiology of fragile X. Also, research in the fragile X field was initially the province of molecular biologists and geneticists, so bringing more neuroscientists into the research community was deemed a high priority. These past efforts have been quite successful, generating detailed insights into the basic biology of fragile X; additionally, fragile X and the normal function of FMRP are both very hot topics in neuroscience today. Thus, basic research into fragile X disease mechanisms can no longer be considered a bottleneck, and it must be considered a lower priority for funding.

Other past bottlenecks in research, such as poor antibodies to FMRP and difficulties obtaining animal models, have been resolved by specific resource grants by FRAXA (some continuing to the present). This has enabled an explosion in translational research in fragile X, leading to many promising therapeutic strategies in the works.

However, this also had the net effect of moving the bottleneck further down the road, to the preclinical validation stage of the development process. Many labs have difficulty testing drugs in live animals quickly and cost-effectively. Also, we have come to appreciate that therapeutic strategies can demonstrate effectiveness in fragile X models, but since there are many different disease mechanisms at work in this complex disorder, these treatment strategies may only be addressing a small part of a much larger whole.

In response, FRAXA has developed new methods of validating promising drug treatment strategies in a standardized manner, with much higher through-put and vastly greater efficiency. Thus, we are less likely to fund academic labs for years on end to test one particular drug strategy — this approach, though appropriate in the past, is too inefficient for the task moving forward. With the bottleneck at the preclinical validation stage of development essentially resolved, the new bottleneck down the road is now at the clinical trials stage.

Best of luck!

Michael Tranfaglia, MD
Medical Director, FRAXA Research Foundation

Fragile X Research Grants: How to Apply

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Genes and Gems Fundraiser raises $40,000 for Fragile X Research

On April 8, our fabulous friends of FRAXA in Ohio put on another great show as they held their Genes and Gems fundraiser at the St. Charles Preparatory School in Columbus. It was a night to bring together over 300 families, friends and supporters of fragile X research. The event included an inspiring presentation by the well-loved local fragile X physician and researcher, Dr. Craig Erickson, from Cincinnati Children’s Hospital. From the great conversations, delicious food, and the silent and live auctions (including a ride on the Goodyear Blimp!), it was clear that everyone had a wonderful time.

Dr. Craig Erickson - Fragile X research
Genes and Gems for Fragile X Research

We want to thank all those who attended Genes and Gems and made generous donations to the FRAXA Research Foundation. A very special thanks to the Planning Committee for their tireless work and commitment to putting on this special event.

The Barden Family
The Heiman Family
The Frederick Family
The Lafferty Family
The Mack Family
The Maloney Family
The McCollister Family
The Meyers Family

The evening festivities raised $55,000, and after expenses of $15,000, this means $40,000 will go directly to research to find a cure for fragile X! In addition, Brett Livingston and Riley Maloney organized FRAN for FRAXA, a companion CrossFit event in Lewis Center, OH, on April 29, which boosted the total even more!

genes and gems for fragile X

TD Bank invites friends of FRAXA to watch the Bruins

Fifty friends of FRAXA enjoyed an amazing night at the TD Garden in Boston on March 30. They gathered to watch the Boston Bruins take on the Dallas Stars. It was a great opportunity for us to unite the greater Boston fragile X community. We were able to convene and thank some of our local families and introduce them to university and biotech scientists who are working to find a cure for fragile X.

The night was made available by a generous donation of the Garden View Room by TD Bank.

Friends of FRAXA, Bob Sweeney, President of the Boston Bruins Foundation

Many children with fragile X were able to join in, including Preston who enjoyed the special treat of riding the Zamboni around the ice after the second period!

Another happy participant was Eric, whose mom, Clare, wrote:

Seeing a game with my husband and son at the Garden was priceless. Eric was able to get up and walk around the box and so many SMILES were sent his way! I looked at other parents looking at him as he did some of his hand flaps and awkward body movements, and their soft smiles let me know we were in a safe place to enjoy a magical evening.

Although Eric didn’t interact with the other children with fragile X there, we made a point of showing him others who share his diagnosis. That’s powerful stuff!!

A big Thank You from us to TD Bank and the Bruins and especially player Frank Vatrano. Eric was too anxious to go up to greet him but Frank’s signed hockey stick is currently in his bed next to his pillow! We will cheer for him extra hard when we see him on the ice.

All of us at FRAXA are grateful to TD Bank and the Boston Bruins for making this a very special night. Thank you also to Bob Sweeney, President of the Boston Bruins Foundation, for stopping by and for your ongoing support.

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

 

Dave Bjork named Director of Development at FRAXA

FRAXA Director of Development Dave BjorkNewburyport, MA — FRAXA Research Foundation, the world’s only organization solely committed to finding a cure for fragile X syndrome, the leading known inherited cause of intellectual disabilities and autism, has named Dave Bjork to the newly created position of Director of Development.

Bjork, of Georgetown, Mass., has more than 17 years of progressive experience in nonprofit marketing and fundraising leadership roles including Vice President of Development, National Foundation for Cancer Research, Bethesda, MD. In this role, he launched several fundraising programs and became known as the “Cancer Research Evangelist” because of his dedication and commitment to basic scientific research. Bjork has made it his life mission to connect individuals, businesses, academic institutions and other key influencers to forge strong partnerships to focus on researchers being funded so they can deliver life changing advances. “Funding research directly and fully is the most powerful way to cure disease,” said Bjork.

“I am thrilled to welcome Dave to our organization,” said Katie Clapp, President/Cofounder, FRAXA. He brings incredible energy, experience and enthusiasm and his passion is palatable. He will lead our efforts to raise awareness and more funds to find a cure for fragile X.”

Bjork earned a BS in Economics and Finance from the Wharton School at the University of Pennsylvania.

You can reach Dave at dbjork@fraxa.org or (978) 462-1866.