080210xf's Blog

L'X fragile sera vaincu | Fragile X will be conquered

Archive for May, 2011

Autistic children use iPad at Toronto school to reach out and communicate

By Pat Hewitt, The Canadian Press

TORONTO — Four-year-old Satu Kuisma smiles as she finds a picture of herself and touches it on the screen.

When teacher Sabrina Morey asks the kindergartner to tell her what she did in class that day, Satu taps away on the iPad, selecting pictures for eating, drawing and playing on swings.

Communication can be a struggle for Satu, who has a rare chromosome disorder. Born at just 2 1/2 pounds, she has had developmental delays, one of the most prominent being her speech. But she’s among dozens of non-verbal children at a Toronto school who are learning to communicate through touch technology.

Satu and the other students at the Beverley School are involved in a research project with University of Toronto professor Rhonda McEwen aimed at determining if devices like iPads make it easier for developmentally challenged children to communicate and interact with others.

So far, McEwen says, the answer is yes.


Seaside Therapeutics Publishes Review of Advances in the Treatment of Fragile X Syndrome in American Chemical Society Chemical Neuroscience

— Research Highlights Paradigm Shift in Drug Development for Neurodevelopmental Disorders Facilitated by New Understanding of Fragile X Syndrome Pathophysiology —

CAMBRIDGE, Mass.–(BUSINESS WIRE)–May 18, 2011 – Seaside Therapeutics today announced the publication of a review paper detailing the evolving scientific and drug development landscape for fragile X syndrome, the most common inherited form of intellectual disability and the most common known cause of autism. The cognitive impairment associated with fragile X syndrome and other intellectual disabilities has long been considered permanent and untreatable, and drug development efforts have largely focused on relieving the symptoms of these disorders rather than correcting the underlying cause(s). This review article draws upon more than 100 studies to propose a paradigm shift in the approach to drug development for intellectual disabilities based on a new-found understanding of the core pathophysiology of fragile X syndrome. This paper highlights a number of recent scientific advances in understanding the genetic and biologic causes of fragile X syndrome, which are informing the development of novel therapeutic candidates to address the root cognitive deficits of fragile X. This work may have application to the treatment of other neurodevelopmental disorders.

The paper, “Fragile X Syndrome (FXS) – an update on developing treatment modalities,” was published online in the journal ACS Chemical Neuroscience and includes a discussion of the mGluR theory of fragile X syndrome. This theory is based on research suggesting that inhibition of group I mGluR signaling reduces protein synthesis and, in turn, may correct the cognitive and behavioral phenotypes associated with fragile X syndrome. Multiple genetic and pharmacologic studies support mGluR5 inhibition as a promising therapeutic opportunity, providing compelling evidence that altering mGluR5-dependent protein synthesis may directly affect the synaptic alterations underlying the fragile X phenotypes. Additionally, the importance of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system, has recently emerged and been show to oppose the action of mGluR5, providing a novel mechanism for therapeutic inhibition. Studies examining induced seizure activity in mice suggest that the opposing actions of mGluRs and GABA-B receptors provide a therapeutic path for fragile X syndrome. This novel insight reinforces the potential for GABA-B agonists like Seaside Therapeutics’ drug candidate STX209 to counter the effects of mGluR5 in fragile X syndrome and possibly correct specific deficiencies in GABA neurotransmission. This finding could have broad applications in research to treat intellectual disability.

Dr. Aileen Healy, Vice President of Research at Seaside commented, “We are now beginning to believe that intellectual disability is not, as previously understood, an immutable condition. Translating our understanding of the biological effects of key genetic mutations has revealed a variety of promising mechanistic approaches to treat fragile X syndrome, which I believe represent an exciting opportunity to realize the mission of developing effective therapeutics for patients in need.”

About STX209:

STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist. Pathologies observed in certain neurodevelopmental disorders, including fragile X syndrome (FXS) and autism spectrum disorders (ASD), are believed to be caused by excessive activation of glutamate receptors and abnormally high ratios of excitatory to inhibitory neurotransmission in the brain. GABA-B receptors play an important role in modulating the release of glutamate and maintaining the optimal excitatory-inhibitory balance. STX209 has demonstrated efficacy in preclinical models, suggesting that the functional deficits of individuals with FXS and ASD may be ameliorated by modulating glutamate release and optimizing the ratio of excitatory to inhibitory neurotransmission.

STX209 has successfully completed the largest ever randomized, blinded, placebo-controlled trial (Phase 2) in patients with fragile X syndrome and an open-label Phase 2 exploratory trial in patients with autism spectrum disorders. Later stage trials in both indications are expected to begin by summer 2011.

About Fragile X Syndrome:

Fragile X syndrome is a neurodevelopmental disorder characterized by impaired social function, cognition and speech, as well as attention deficits and low functional independence. It is the most common inherited form of intellectual disability and affects roughly 100,000 individuals in the U.S. It is also the largest known cause of autism. Fragile X syndrome is caused by a mutation of a single gene, the Fragile X mental retardation 1 (FMR1) gene, on the X chromosome. The FMR1 gene produces a protein needed for normal brain development. Individuals with fragile X syndrome lack this protein and, as a result, the majority of affected individuals will have significant intellectual disabilities, requiring life-time care. To date, there are no approved treatments for this disorder. The FDA has designated fragile X syndrome as an orphan disease.

About Seaside Therapeutics:

Seaside Therapeutics, Inc. is creating novel drug treatments to correct or improve the course of fragile X syndrome, autism and other neurodevelopmental disorders. The Company is dedicated to translating breakthrough discoveries in neurobiology into therapeutics that improve the lives of patients and their families. For more information please visit www.seasidetherapeutics.com.

Mark Bear: Charting New Waters

Entrevue avec Mark Bear, auteur de la théorie des mGluR, théorie en amont des études cliniques en cours dans le syndrome du X fragile (avec les antagonistes mGluR5 et l’arbaclofen), théorie annonciatrice, aussi – espérons-le – d’un changement de paradigme dans le traitement de la déficience intellectuelle d’origine génétique.


By Madeline Drexler, hhmi.org |


Mark Bear—a champion helmsman and neuroscientist at the Massachusetts Institute of Technology—says he applies the same principles to racing and research.

“You begin with probabilities. You don’t know a priori whether heading off to the left side of the racecourse or the right is the way to go. So you collect information, make observations, test hypotheses. You do a few pilot experiments, sailing upwind a little in either direction, to see what looks promising. You make a plan, and take measurements of whether or not the plan is working. If you made a wrong guess, you make on-course corrections.

“But what really separates great sailors from less great sailors,” adds the HHMI investigator, “is that they see things that other people don’t.”


Fragile X and Rett Syndrome – Opposite Ends of the Bell Curve?

Rettsyndrome.wordpress.com |

Mark Bear, Ph.D. of MIT is the most recent addition to RSRT’s portfolio of funded scientists. Prof. Bear studies “synapses” the gaps between nerve cells where chemical or electrical signals are exchanged. The strengthening and weakening of synapses contributes to learning and memory but when impaired can lead to neurological disorders.

Much of the excitement in the Fragile X community comes courtesy of the Bear lab. His discoveries have spawned a series of clinical trials.
New York Times

Monica Coenraads, Executive Director of RSRT, recently caught up with Prof. Bear to discuss his Fragile X research and how it might extend to Rett Syndrome.

MC: Prof. Bear, thank you for taking time to discuss your research with us. Many of our readers will have heard of the ongoing Fragile X clinical trials and are eager to understand how your research might also impact Rett Syndrome. Please explain the so called “mGluR Theory of Fragile X” which was discovered in your lab.

MB: Sure. Synaptic function requires the synthesis of proteins in the synapses, so that supply can keep up with demand.  Demand is registered, in part, by activating metabotropic glutamate receptors (mGluR).  So the more active the synapses are, the more glutamate is released and the more protein is made. Like in many systems there are checks and balances, and one of those is the negative regulation of protein synthesis by FMRP, the protein made by the Fragile X gene, FMR1.  Normal synaptic function requires a sense of balance between driving protein synthesis through mGluRs, and inhibiting protein synthesis through FMRP. In Fragile X the FMRP protein is missing so it’s like driving a car with no brakes – your foot is on the gas but there is no way to stop. So there’s excessive protein synthesis which leads to a myriad of deleterious consequences. The approach that holds a lot of promise is to inhibit mGluR which in essence takes your foot off the gas.

Now that theory has been pretty widely validated and at least in the animal models of Fragile X  many features of the disorder can be corrected by inhibiting mGluR.

MC:  You theorize that Rett Syndrome is at the other end of the spectrum, instead of too much protein synthesis, there’s too little protein synthesis. What’s behind this hypothesis for you?