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

Archive for x fragile

Workings of brain protein suggest therapies for inherited intellectual disability, autism

Cell Press via Eureka Alert |

Researchers now have a much clearer understanding of how mutations in a single gene can produce the complex cognitive deficits characteristic of Fragile X Syndrome, the most common inherited form of intellectual disability. As the majority of patients with Fragile X Syndrome also display autism-like symptoms, the findings offer hope for treating both conditions.

A report in the July 22nd issue of the journal Cell, published by Cell Press, defines a set of messenger RNA (mRNA) molecules that the Fragile-X mental retardation protein (FMRP) binds in the brains of mice. Many of these mRNAs encode proteins that function at neurons’ connection points. When properly bound, FMRP prevents the translation of these mRNAs into proteins until the time is right.

“By understanding for the first time the direct targets of FMRP and its actions, we open up a whole world of potential avenues for therapies designed to make kids with Fragile X or autism better,” said Robert Darnell, a Howard Hughes Medical Institute investigator at The Rockefeller University.

“The power comes from taking two diseases with similar symptoms and looking at what is in common,” added Jennifer Darnell, also at The Rockefeller University. Of the almost 850 identified targets of FMRP, she explained, it is likely only a much smaller subset has a real impact on health or disease.

The Darnell team’s breakthrough uses a technique they developed a few years ago based on a “biochemical trick”. They use ultraviolet light to solidify the bonds between a protein, in this case FMRP, and the mRNAs it binds. Those protein-mRNA complexes could then be isolated and sequenced to reveal a “beautiful map” of the mRNA transcripts and precisely where they are bound to FMRP.

The experiments reveal that FMRP specifically binds to the protein-coding portions of those brain mRNAs. Jennifer Darnell said that distribution is unlike what they’ve seen before and looked much like the distribution of ribosomes, the cellular components that assemble proteins.

Further experiments suggest that FMRP acts as a “brake,” reversibly stalling ribosomes after they bind mRNA. Robert Darnell likened FMRP to the nozzle at the end of a hose. It allows the mRNA transcripts to be loaded with ribosomes in the locations where they will be needed, and when the time is right, bursts of translation (protein synthesis) can occur. That sort of tight control is likely to be critical for the formation and plasticity of neural connections, the cellular foundation for learning and memory.

Their basic scientific discoveries suggest two different overall strategies for treating Fragile X Syndrome: by lowering the activity of particular proteins normally kept under wraps by FMRP or by replacing FMRP’s ability to stall ribosomes. Notably, the Darnells say the latter is exactly what antibiotics do to slow the growth of bacteria.

“We may be able to take the edge off of the extra protein synthesis,” Jennifer Darnell said.

Ultimately, there will be more to the story, Robert Darnell added. “FMRP is one of many regulatory proteins in the neuron. It doesn’t work all by itself.”

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New research aims to shed light on abnormal brain development

Via Eurekalert |

Vancouver, BC – Local researchers are finally on the road to developing targeted treatments for serious, life-long disabilities such as autism and schizophrenia, thanks to new genomics research focusing on abnormal brain development.

With funding from Genome British Columbia, Dr. Daniel Goldowitz of the UBC Department of Medical Genetics and the Centre of Molecular Medicine and Therapeutics, is opening the mysterious world of the developing brain by mapping the genes in the cerebellum and studying which genes influence abnormal development.

The $330,000 (CDN) project, Functional Characterization of the Transcriptional Network Driving Mammalian Brain Development, will determine which genes are activated and essential during brain development so researchers can better understand development-related diseases such as autism spectrum disorder, schizophrenia and fragile X mental retardation. One key to understanding these disorders lies in the study of a region of the brain that has been difficult to map, the cerebellum.

If the researchers can identify key genes involved in the early development of the cerebellum and that influence the rest of brain development, they may be able to encourage or restart plasticity, the brain’s ability to heal and change. These discoveries are anticipated to lead to new drugs and cognitive treatment for people with abnormal brain development.

“All of our incoming sensory information is received by the cerebellum where it can be compared and contrasted,” says Goldowitz. “So you can imagine if there is a mismatch between information coming in and going out – that there would be a serious problem. You might create another world to try and help you cope like with schizophrenia, or within autism you might shut down incoming information to cope.”

“Our long term goal would be to develop tools for early diagnosis of, and possible therapies for brain disorders such as autism,” says Goldowitz. Increased knowledge and understanding of the genetic wiring of the cerebellum will also open the door to new therapeutics for deadly childhood brain cancers.

Working in close collaboration with Dr. Harukazu Suzuki and colleagues at the world-renowned RIKEN Institute in Japan, the researchers will use cutting-edge genomic technology to identify gene regulatory networks, which control how the cerebellum develops.

The partnership with the RIKEN Institute will allow the researchers to capitalize on world-leading genomic technologies to study the gene expressions and interactions of the cerebellum at a level of resolution never before attained.

“Up until now, we couldn’t manage the data sets because they were just too large,” says Goldowitz. “Through with this international partnership, we should be able to see which genes are turning on other genes so that we can build networks that show the architecture of the developing cerebellum.”

“Genome BC is pleased to support this innovative and exciting research in brain development,” says Dr. Alan Winter, President and CEO of Genome BC. “This is exciting on many levels. It offers promising new therapies for developmental and neurological disorders and makes practical use of the latest genomic technologies. In addition, it extends BC scientific excellence into new international collaborations with esteemed researchers at the RIKEN Institute in Japan.”

Genome BC has funded this project as part of its Strategic Opportunities Fund, which funds projects with direct impact on industry and other end-users.

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Seaside Therapeutics Advances Fragile X Drug

By Lisa Jarvis, cenblog.org |

Some great news out today for parents of kids with Fragile X, a neurological disorder that is also the most common genetic cause of autism: Seaside Therapeutics has begun a Phase III trial of STX209, which could potentially be the first drug available to treat the underlying symptoms of the disorder.

Fragile X, a disorder that, like autism, impacts the way brain cells communicate, is caused by a mutation to the FMR1 gene. People with Fragile X suffer from over-stimulated synapses, creating a kind of signaling noise that prevents them from easily learning through experience.

STX209 is a single-isomer version of the already-approved muscle-relaxant baclofen, a GABA-B receptor agonist. It was identified as a potential treatment for Fragile X after doctors noticed a child who was given the drug to treat a gastrointestinal problem also showed improvements in cognitive function and behavior. Seaside separated out the two isomers and found the efficacy in one isomer and the majority of the negative side effects in the other.

Those following drug development in Fragile X know that both Novartis and Roche have seen promising results in small Phase II trials of compounds that act like a brake on mGluR5, a neurotransmitter receptor that MIT neurologist Mark Bear found to be overstimulated in people with Fragile X. STX209 works by dampening the activity of mGlur5, although the Seaside has another compound in development that works directly on the protein.

Seaside expects to sign up 120 people, ages 12 to 25, with Fragile X, in its Phase III trial, and start a second study for kids ages 5 to 11 in early summer. The trial ages are notable because the Novartis and Roche trials were both conducted on adults ages 18 and up; because the side effect profile of baclofen is well understood, FDA has been willing to allow STX209 to be tested in children.

The continued success of the drug could have implications for the broader autism community. Seaside has already begun testing STX209 in autism with the idea that some of the neurological breakdown could happen along that mGluR5 signalling pathway. And although the trial was small—and was open label, meaning doctor’s knew the kids were getting the drug—the biotech firm was encouraged to see signs of similar improvements in social behavior and cognition as in the Phase II study in Fragile X.

Ultimately, Seaside hopes to develop drugs for other single-gene mutations with links to autism, with the hopes of helping both those patients as well as the broader autism population. The story is still evolving, but it’s encouraging nonetheless to see some good news in a area that is seriously in need of new treatments.

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Seaside Therapeutics commences STX209 Phase 3 study in fragile X syndrome

Via news-medical.net /Published on June 2, 2011 at 8:19 AM |

Seaside Therapeutics, Inc. announced today the initiation of a randomized, double-blind, placebo-controlled Phase 3 study to evaluate the effects of STX209 (arbaclofen) on social impairment in adolescents and adults (ages 12 to 25) with fragile X syndrome. A second study in children (ages 5 to 11) is expected to begin in early summer. STX209 is an oral selective gamma-amino butyric acid type B (GABA-B) receptor agonist.

“STX209 may be able to play a much needed role in improving the core symptoms of fragile X syndrome and in helping patients and their families achieve an improved quality of life,” said Randall L. Carpenter, M.D., President and Chief Executive Officer of Seaside Therapeutics. “In our Phase 2 study, we were very excited to observe clinically meaningful improvements in social impairment in patients receiving STX209—marking the first time a drug candidate has positively impacted a core symptom of fragile X syndrome. The Phase 3 study is the most comprehensive study ever undertaken in patients with fragile X syndrome and represents the first time that a drug candidate will be evaluated for a core symptom of fragile X syndrome as the primary endpoint.”

Source: Seaside Therapeutics

ADHD, autism or something else entirely?

Theconversation.edu.au |

Most people are not aware of fragile X syndrome but they may well be affected by it or know someone who is. Commonly under-diagnosed or misdiagnosed the condition is often mistaken for Attention Deficit Hyperactive Disorder (ADHD) or autism.

Prevalence of 1 in 2500 worldwide makes the syndrome the world’s most common cause of hereditary developmental difficulties in children.

Its effect is gender-specific with girls usually showing milder levels of intellectual difficulty than boys.

Caused by an abnormal expansion of DNA just above the tip of the X chromosome’s long arm, fragile X occurs across every culture. And unlike similar disorders, it is not related to the age of the mother at the time of conception.

Genetic path of the syndrome

Fragile X can be inherited from either a mother or father carrying an abnormal copy of the gene on their X chromosome.

Since the gene is on the X chromosome, a father cannot pass it on to his sons (fathers only pass on a Y chromosome to male offspring).

When the fragile X gene is passed on from a mother to her children, the gene may become altered to the point where it is unable to work properly. When this happens the gene cannot produce enough or any of the protein coded for it.

Although the exact function of this protein is not yet full understood, it is known to be critical to early intellectual and cognitive development. So the most prominent feature of fragile X is developmental difficulties.

The autism-fragile X link

One of the reasons why a diagnosis of fragile X is often delayed is because it shares many characteristics with autism.

Current research estimates that 25% to 35% of children who have fragile X are misdiagnosed as having autism due to the disorders’ many overlapping features.

Features common to both include language delay, echolalia, and repetitive speech alongside poor eye contact, and stereotypic movements such as hand biting and hand flapping.

Many children also display unusual reactions to environmental stimuli such as sudden noises e.g. sirens or alarms, movements, or changes such as a transition from one classroom activity to another.

The anxiety this provokes can often lead to hyper-arousal potentially leading to outbursts of aggression.

Common behavioural challenges in people with fragile X

Alongside hyperarousal, hypersensitivity is another early prominent behavioral feature in boys and girls with fragile X syndrome.

Children may become overwhelmed by the demands created by social involvement, novel or unexpected situations and changes, even the common transitions of daily life.

Another distinct and pervasive behavioral feature of the syndrome are attention and hyperactivity problems.

In the classroom, these behaviours can manifest themselves as difficulty in staying focused on a task for more than a few moments, difficulty in following very simple instructions, easy distraction by sudden noises or movements (e.g. scraping of a chair) and extreme impulsiveness.

The severity and prominence of these behaviours often contribute to a clinical diagnosis of Attention Deficit Hyperactivity Disorder (ADHD).

Another symptom is extreme shyness, which is experienced by many people with fragile X, especially girls, and can often hinder the desire to initiate friendships in childhood and adolescence.

The importance of accurate diagnosis

Misdiagnosis of children with fragile X denies them access to syndrome-specific resources and support systems. These would be most beneficial in early school years when intervention is most effective.

The physical features, social, behavioural and academic impairments present in people with fragile X differ from those with autism and ADHD so early intervention is doubly important.

Recognizing these features is critical to help clinicians properly diagnose the syndrome as early as possible in development so effective educational and clinical interventions can be implemented from a young age.

It is also important that resources are available for teachers from as early as preschool so that at every stage of academic transition, teachers and parents alike know what to expect and how to intervene with fragile X-specific educational resources.

The proposed development of “Building Links Australia” a virtual web resource for families, educators and clinicians will help create partnerships in understanding, intervening and treating children and adolescents with fragile X and other developmental disabilities across the academic trajectory.

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Wisdom teeth and stem cells

ATLANTA — “Families that have children with special needs are desperately seeking answers.” And one of the last places Gail Heyman ever thought to look was in her son’s mouth. But there in the back, in the aptly named wisdom teeth, answers for researchers at Emory.

“Scott was not diagnosed until he was 9 years old.”

Scott Heyman has Fragile X, a genetic disorder. Scott’s mother Gail says, “Fragile X is the leading cause of mental impairment that is inherited.”

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Neuroscience drug discovery center opens at Vanderbilt

by Bill Snyder | Posted on Friday, Mar. 11, 2011 — 2:55 PM

(…) With Seaside Therapeutics in Cambridge, Mass., the team is trying to “tune down” excessive signaling through two different pathways. The goal is to relieve – for the first time with a drug – learning, memory, social and behavioral problems associated with Fragile X syndrome, the most common inherited form of mental retardation and the most common genetic cause of autism. (…)

L’X fragile sur M6 | Santé : Vincent, 16 ans, “X fragile”

Santé : Vincent, 16 ans, “X fragile”…
On compte jusqu’à 8.000 maladies rares. Des maladies dont les noms sont parfois très énigmatiques tel que le syndrome de l’X fragile, qui touche en majorité des garçons. Parmi eux : Vincent, 16 ans, qui, malgré le handicap, s’accroche à son rêve…
Vidéo ici

Congrès scientifique international sur l’X fragile à l’Institut Pasteur, Paris :24 26 mars prochain

Sous la présidence d’honneur de Randi Hagerman, du MIND Institute, CA, USA |

Chers Collègues,Chers Amis,

Je suis très heureuse de vous inviter aux deuxièmes Journées Internationales Jérôme Lejeune (JIJL), qui auront lieu à Paris, à l’Institut Pasteur. Cette conférence, organisée par la Fondation Jérôme Lejeune, réunira médecins, chercheurs et professionnels de santé autour d’un thème important et en pleine expansion : Déficience intellectuelle d’origine génétique : progrès vers des traitements ciblés

En effet, au cours des dernières années, voire même des derniers mois, la recherche sur le déficit intellectuel a fait un bond en avant spectaculaire, de la souris à l’homme, particulièrement dans le domaine thérapeutique. Des experts de haut niveau nous donneront leurs informations sur les enjeux généraux et spécifiques de la thérapeutique appliquée à la déficience intellectuelle. Notre programme scientifique met l’accent sur les nouveautés dans la recherche en biologie moléculaire, génétique, neurobiologie et neuropsychologie conduisant à de nouveaux essais thérapeutiques dans de nombreux désordres du neuro-développement. Les traits communs à ces désordres du neuro-développement seront mis en évidence et il est probable que nombre de traitements exposés seront utiles à plus d’une pathologie.

Ces trois journées de conférence permettront aux chercheurs et cliniciens d’échanger sur leurs connaissances et leurs idées et de stimuler des collaborations dans le domaine des thérapeutiques du futur.

Une exposition de posters présentera les travaux récents sur ce thème riche et intéressant. A la fin de la conférence, des prix seront remis aux deux meilleurs posters, ceci afin de souligner les étapes clefs réalisées dans le traitement des patients atteints de déficit intellectuel.

Nous souhaitons que cet évènement vous apporte l’information scientifique la plus récente possible, ainsi que les suggestions et contacts les plus utiles à votre activité professionnelle.

Dans cette perspective, je me fais une joie de vous accueillir à Paris pour ces trois journées.

Professeur Randi HAGERMAN
Présidente du Comité Scientifique
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Researchers win congressional grant to study fragile X

$3M grant will fund efficacy tests of new approach to treating children with fragile X, the most common single-gene cause of autism.

Three internationally respected UC Davis researchers — two expert in fragile X syndrome and one in epilepsy — have joined forces to test the efficacy of an innovative new approach to treating children with fragile X, through a $3 million grant from the U.S. Congress.

The researchers will explore the safety and effectiveness of a synthetic neuroactive steroid drug, ganaxolone, for treating the anxiety that is common in children with fragile X, a condition that is the leading cause worldwide of inherited intellectual disability and the most common single-gene cause of autism. The collaboration includes Randi Hagerman, an international authority on fragile X-related disorders, Michael Rogawski, known worldwide for his epilepsy research, and David Hessl, an expert in psychophysiologic studies.

“We believe that this drug will be highly effective for treating the anxiety, inattention and impulsivity in children with the full fragile X syndrome mutation,” said Hagerman, who is medical director of the UC Davis MIND Institute and treats people with fragile X syndrome. “This compound opens up a whole new avenue of treatment for people with fragile X.”

Fragile X syndrome is the result of a defect on the X chromosome. It is estimated to affect 1 in 3,600 males and 1 in 4,000 females. One-third of all children with fragile X syndrome develop autism and approximately 5 percent of children with an autism-spectrum disorder have fragile X.

“In fragile X syndrome, in addition to the intellectual disability, there is a range of learning disabilities and other neurological problems such as seizures,” said Rogawski, who is chair of the UC Davis neurology department. “Ganaxolone originally was developed to treat epilepsy and has anti-seizure and anti-anxiety properties.”

For the study, the researchers will enroll 60 children between the ages of 6 and 17 years over a four-year period. Participants initially will receive either ganaxolone or a placebo and then after six weeks will receive the opposite medication, ganaxolone or a placebo. The effects will be studied through a variety of tests and outcome measures, including eye-tracking to determine children’s ability to make eye contact and levels of hyperactivity. The drug will be provided by Marinus Pharmaceuticals.

Funding for the study is provided by the Department of Defense Peer-Reviewed Medical Research Program of the Congressionally Directed Medical Research Program.

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New drug rescues function in fragile X syndrome

Deborah Rudacille, Sfari.org |

A new drug appears to relieve symptoms of fragile X syndrome by blocking the over-production of a key protein in a subset of people with the disorder, according to a 6 January study in Science Translational Medicine1.

Fragile X syndrome, an inherited form of mental retardation with features of autism, is caused by a mutation in the FMR1 gene. Some individuals with fragile X have the full mutation, which shuts down production of the protein, FMRP, needed to form healthy connections between neurons. Others have a partial mutation, which spares some FMRP production.

FMRP acts as a brake on components of the mGluR5 pathway, which run riot in individuals with the full mutation, leading to severe symptoms of the disorder. The new study shows that the drug AFQ056, made by Swiss pharmaceutical giant Novartis, blocks production of mGluR5, lessening the severity of symptoms in individuals with the full mutation. Individuals with partial mutations show more variable results.

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Une molécule pour combattre à la racine une forme de retard mental et d’autisme

Nadine Richon/Unicom |
Une étude européenne menée par Sébastien Jacquemont, au Service de génétique médi-cale CHUV-UNIL, montre avec un essai réalisé dans le cadre d’un partenariat académi-que et industriel que des améliorations sont possibles pour des patients atteints de trou-bles intellectuels jugés irréversibles.

Forme la plus fréquente de retard mental hérité, le syndrome de l’X fragile intéresse les cher-cheurs depuis de nombreuses années comme modèle monogénique pour l’étude du retard mental et de l’autisme. Cette maladie sous-diagnostiquée (un enfant sur 4000) se manifeste par une anxiété, une hyperactivité et des traits autistiques, les patients souffrant d’une incapa-cité à traiter les informations sensorielles. La découverte sur le chromosome X du gène FMR1 dont la mutation est responsable de la maladie date de 1991, mais personne jusqu’ici n’avait réalisé d’essai thérapeutique ciblé non pas sur un symptôme, par exemple l’anxiété, mais sur les mécanismes mêmes de la pathologie.

En collaboration avec Novartis, Sébastien Jacquemont et ses collaborateurs suisses et euro-péens ont traité 30 patients avec la molécule AFQ056. Celle-ci freine spécifiquement l’activité des récepteurs MGluR5 (metabotropic glutamate receptor 5), essentiels au bon fonc-tionnement cérébral. En effet, absente chez ces patients, la protéine FMRP ne remplit plus sa fonction de régulation de ces récepteurs. Grâce à ce «frein médicamenteux», certains enfants ont interagi davantage avec leurs proches, qui ont pu constater ainsi des améliorations impor-tantes de leur comportement.

Il se trouve que les patients concernés par ces améliorations partagent une spécificité généti-que : chez eux, le gène FMR1 muté est totalement désactivé. Appelée methylation, cette mo-dification chimique de l’ADN conduisant à l’inactivation complète d’un gène pourrait donc servir de bio-marqueur pour déceler les patients capables de répondre à ce type de traitement.

Publiée dans la revue Science Translational Medicine, cette étude représente un premier pas significatif pour le diagnostic et le traitement ciblé de l’X fragile, voire d’autres retards men-taux. Parmi les étapes suivantes, les mêmes équipes évaluent les effets à plus long terme sur le comportement et la cognition avec des essais en cours cette année au CHUV. Dans un futur à moyen terme, il s’agit d’étudier les bénéfices de cette molécule pour des sous-groupes d’enfants autistes. En effet, il est probable que certaines formes d’autisme partagent avec le syndrome de l’X fragile des mécanismes physiopathologiques similaires. «On a trop long-temps considéré les retards mentaux comme des troubles du développement irréversibles. Il est temps d’envisager des prises en charge spécifiques s’attaquant à la cause et pas seulement aux symptômes de ces maladies», souligne le Dr Sébastien Jacquemont.

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AFQ056 | INTERVIEW DU PR VINCENT DESPORTES – 2011

Les conclusions très encourageantes d’un essai clinique européen sur l’X fragile viennent d’être publiées dans la revue Science translational Medicine. Le Pr Vincent des Portes, co-auteur de cette publication et membre du Conseil scientifique de la Fondation Jérôme Lejeune, a bien voulu nous éclairer sur cette étude.

INTERVIEW

L’X Fragile fait-elle partie des maladies rares et quels en sont les symptômes ?

L’X Fragile, qui touche un garçon sur 5000 et une fille sur 9000, est la première cause héréditaire de déficit intellectuel (la trisomie 21 étant la 1e cause génétique de déficit intellectuel). Outre une déficience intellectuelle parfois importante, cette affection génère des troubles comportementaux assez caractéristiques tels que hyperactivité, anxiété, comportements répétitifs, parfois auto agressivité, qui parasitent la vie quotidienne. Ces symptômes sont liés à un défaut de filtrage des stimuli sensoriels et émotionnels.

En quoi consiste le médicament qui vient de faire l’objet d’un premier essai clinique chez le patient ?

C’est le blocage de l’expression du gène FMR1, porté par le chromosome X, qui est à l’origine de cette pathologie. Cette anomalie empêche la production du produit de ce gène, la protéine FMRP. Cette dernière étant inactive, elle ne peut pas réguler les récepteurs mGluR5, qui utilisent le glutamate, l’un des principaux neuromédiateurs dans le cerveau. Le médicament que nous avons testé – AFQ056 –, est un antagoniste spécifique des récepteurs au glutamate de type mGluR5 qui permet d’atténuer l’hyperexcitabilité de la voie du glutamate bien démontrée dans le modèle souris de cette maladie.

Quels sont les effets du médicament constatés lors de cet essai ?

Son effet sur l’ensemble des troubles comportementaux est apparu très clairement : l’irritabilité et les comportements répétitifs sont diminués, les patients sont apaisés, plus attentifs, plus réceptifs. En revanche, il faudra un essai sur une plus longue durée et davantage de patients pour savoir s’il a un effet direct sur la déficience intellectuelle ou si celle-ci est réduite simplement du fait de la réduction des troubles comportementaux. De manière inattendue, nous avons observé que les patients les plus améliorés étaient ceux chez qui le gène en cause (FMR1) était totalement inactivé ! C’est un argument fort pour espérer que ce médicament cible un mécanisme essentiel et constitutif du syndrome de l’X fragile.

Qui est à l’origine de cette piste thérapeutique ?

C’est une molécule développée par le laboratoire Novartis qui s’est avérée active sur la Souris modèle de l’X-fragile. Novartis a donc sollicité trois équipes cliniques européennes pour conduire l’essai chez l’Homme. Les deux premiers co-auteurs de cette étude sont le Pr Sébastien Jacquemont, de l’Université de Lausanne, et le Dr Aurore Curie, neuropédiatre dans mon service au CHU de Lyon, qui avait en charge la réalisation concrète de ce travail. Quatorze patients, sur la trentaine testée dans le cadre de cette première étude, l’ont été par mon équipe dans le laboratoire CNRS L2C2 à l’Institut des Sciences Cognitives à Bron. Cela a été une expérience humaine très riche, grâce à la confiance des personnes atteintes du syndrome, et la motivation de leurs familles et des associations de parents (Le Goéland, Xtraordinaire) partenaires de cette aventure.

Quelles sont les étapes suivantes prévues pour poursuivre les évaluations cliniques ?

A partir de février 2011, le développement de l’AFQ056 passe en phase 3 avec la collaboration de 22 centres dans le monde, situés notamment aux Etats-Unis, en Australie et dans de nombreux pays européens dont la France (CHU de Lyon et CHU de La Pitié-Salpêtrière à Paris). Plus de 160 patients adultes seront concernés. A l’automne 2011, une étude portant sur des patients adolescents de 12 à 17 ans viendra compléter l’étude sur les adultes.

Voir aussi : http://www.recherchefondationlejeune.org

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How do the Behaviors Seen in Persons with Fragile X Relate to Those Seen in Autism?

The National Fragile X Foundation |

Many parents are confused about their child’s diagnosis. On the one hand, they’ve been told that their child has autism, “autistic spectrum disorder,” or some degree of autistic-like characteristics. In addition, they may have also been told that their child has fragile X syndrome or that he or she is going to be tested for fragile X.

The association between autism and fragile X was first reported by Brown et al. (1982) and was subsequently confirmed by many others leading to an extensive field of research. In discussing this association it is important to remember that autism is defined behaviorally using the criteria of the DSM IV manual which include lack of social reciprocity or responsiveness, abnormal use of language and communication, and a restricted repertoire of activities and interests. Autism is a heterogenous disorder which means that there are several known causes of autism including phenylketonuria (PKU), tuberous sclerosis and 15q duplications. However fragile X is the most common known cause of autism so far identified. Autism is strongly genetic and it is likely that the inheritance of multiple genes predisposing an individual to autism is necessary in many cases for the full behavioral syndrome to be manifested.

The typical features of fragile X syndrome (FXS) i.e. hand biting, hand flapping, poor eye contact, shyness, and social anxiety are probably related to the sensory hyperarousal that has been documented by many investigators including Belser and Sudhalter (1995), Miller et al. (1999), and Roberts et al.(2002). These features are often also referred to as autistic-like features because they can be seen in individuals who have autism without fragile X. Most children with fragile X, however, are interested in social interactions and do not meet the diagnostic criteria for autism.

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Mouse model hints at Alzheimer’s therapies for fragile X

Sfari.org |

Lowering the levels of proteins associated with Alzheimer’s disease can improve symptoms of fragile X syndrome in mice, according to a poster presented Wednesday at the Society for Neuroscience annual meeting.

Fragile X syndrome is the most common inherited cause of cognitive disability, and the most common known cause of autism. It is caused by a mutation in the FMR1 gene, which encodes FMRP, a regulatory protein.

One of FMRP’s targets is amyloid precursor protein or APP. In turn, APP can be processed by the body to form beta-amyloid, the molecule that forms plaques in the brains of people with Alzheimer’s disease.

“Our previous work has shown that amyloid precursor protein and beta-amyloid are increased in FMR1 knockout mice,” says study leader Cara Westmark, associate scientist in pathology and laboratory medicine at the University of Wisconsin.

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Mark Bear’s Fight To Decode Autism

Après avoir fait la Une du New York Times, le 30 avril 2010, l’X fragile et Mark Bear défraient la manchette du magazine Forbes.

After ‘front paging‘ the New York Times, Fragile X makes headlines again, this time on Forbes.

– – –

Robert Langreth, 11.18.10, 01:40 PM EST, Forbes Magazine dated December 06, 2010 |

MIT researcher Mark Bear thinks that some forms of autism and mental retardation may be treatable with drugs already on laboratory shelves.

Mark Bear, 53, has been fixated on understanding the brain since he was 6–when he saw news commentators speculating about John F. Kennedy’s brain functioning after the shooting. He later became a neuroscientist, now at the Massachusetts Institute of Technology, spending most of his career doing basic research on how the brain’s cells form connections during learning.

Today researchers are buzzing about Bear and his radical new theory that offers a real glimmer of hope that some forms of autism may be treatable with drugs. The causes of autism have mystified scientists for decades. It has been blamed on everything from genes to environmental toxins to the discredited concept that childhood vaccines are the culprit.

Bear’s work suggests that a specific class of drug already sitting on drug company shelves may help patients with an inherited disease called fragile X syndrome, a common cause of autism. It hits one in 5,000 kids and causes mental retardation, anxiety and autism-like symptoms. While years of research remain, Bear theorizes those types of drugs might have application beyond fragile X and into autism in general.

In the wake of his results Roche ( RHHBY.PK – news – people ) and Novartis ( NVS – news – people ) have begun testing an old class of experimental anxiety drugs called mGluR5 inhibitors in fragile X patients. Seaside Therapeutics, which Bear cofounded, licensed a similar drug from Merck ( MRK – news – people ) that is set to enter tests in fragile X patients early next year. Another Seaside drug showed promising early results in a study of 28 autism patients. (Bear owns 5% of the company.)

“I have been in this field for 25 years, and these last two years have been the most exciting in my career,” says Randi Hagerman, a developmental pediatrician at the MIND Institute at UC, Davis who is testing several of the drugs.

Bear’s work in fragile X started with a chance encounter a decade ago with Emory University geneticist Stephen Warren, who discovered the gene for fragile X in 1991. Bear gave a speech about how protein production was needed for certain basic cellular processes involved in memory. That grabbed Warren’s attention. He knew that the same gene that caused fragile X also helped control protein production. “After his talk I leaned over and said, ‘I have a mouse you have to look at,'” Warren says.

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