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

Archive for Mark Bear

Studies highlight promise of fragile X treatment

Jessica Wright, 30 April 2012 |

A promising approach to treating fragile X syndrome could benefit people even after the critical window of early brain development, and alleviate core symptoms of autism, according to two studies published this month.

Fragile X syndrome is caused by the loss of a single protein, FMRP, and is characterized by intellectual disability, unusual physical features and hyperactivity. As many as 30 percent of individuals with the syndrome also have autism; however, the underlying biology of fragile X syndrome may be distinct from that of autism.

The first study, published 12 April in Neuron, provides the first published evidence that many symptoms of fragile X syndrome may be reversible after they have developed1.

Although the results were shown only in mice, they suggest that a similar effect might be seen in people with the disorder, researchers say.

“Parents of adult patients have always thought that these kinds of new treatments might be too late for them, but this gives them a lot of hope,” saysRandi Hagerman, medical director of the MIND Institute at the University of California, Davis. Hagerman was not involved in the new study, but is conducting clinical trials for fragile X therapeutics.

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L’X fragile, un retard mental réparable ?

Le MONDE. fr |

Jusqu’ici, les retards mentaux étaient considérés comme irréversibles. Peut-être plus pour longtemps. En traitant par une petite molécule des souris adultes atteintes du syndrome de l’X fragile – la cause de déficience intellectuelle héritée la plus fréquente chez l’homme -, des chercheurs suisses et américains ont corrigé des signes cardinaux associés à ce trouble du développement cérébral : hyperactivité, déficit d’apprentissage et de mémorisation, sensibilité aux convulsions. Des altérations morphologiques cérébrales, tel un excès d’épines dendritiques, ont aussi régressé.

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Clinical trial for fragile X syndrome treatment

health.universityofcalifornia.edu |

UC Davis will participate in a nationwide trial targeting adolescents and young adults with fragile X syndrome.

The UC Davis MIND Institute is participating in a nationwide, multicenter clinical trial of an investigational medication that has shown clinically meaningful improvements in social functioning in adolescents and young adults with fragile X syndrome.

“This investigational drug has the potential to play a much-needed role in improving the core symptoms of fragile X syndrome and helping patients and families achieve an improved quality of life,” said Randi Hagerman, medical director of the UC Davis MIND Institute and the clinical trial lead investigator.

The medication is known as STX209, or Arbaclofen. It is an oral selective gamma-amino butyric acid type B (GABA-B) receptor agonist being developed by Seaside Therapeutics Inc. of Cambridge, Mass., which is sponsoring the trial.

The study will measure the efficacy, safety and tolerability of Arbaclofen for patients between 12 and 25 years of age with fragile X syndrome, who will receive the medication or a placebo followed by a withdrawal period. The UC Davis MIND Institute will enroll 12 participants.

Fragile X syndrome is the leading genetic cause of intellectual disability and the leading single-gene cause of autism. It is the result of the 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 have significant intellectual disabilities and require lifetime care.

There currently are no Food and Drug Administration (FDA)-approved treatments for patients with fragile X syndrome.

For further information concerning the clinical trial, please contact Lindsey Partington at (916) 703-0471 or lindsey.partington@ucdmc.ucdavis.edu.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.

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From kittens to Fragile X: Do all autisms share a common thread?

Researchers at Children’s Hospital Boston and the Massachusetts Institute of Technology collaborate to learn more about the neurological underpinnings of autism.

By Mustafa Sahin |

Mark Bear’s research interests have taken him from studying vision in kittens to learning and memory in mouse models, and more recently, to the study of Fragile X syndrome, one of the leading genetic causes of autism and intellectual disability in humans.

Along the way, he has made several ground-breaking contributions to neuroscience – one of which he described as one of MIT’s presenters at this week’s inaugural CHB-MIT Research Enterprise Symposium, which kicked off an exciting new scientific collaboration between MIT and Children’s.

I have followed Mark Bear’s work since I was an undergraduate at Brown University, where he used to teach the Introduction to Neuroscience course.

That’s where I first learned about the seminal experiments in kittens (see this PDF), showing that covering one eye at birth rewires their brains not to “see” out of that eye, work that Bear was continuing to refine. Our paths crossed again more recently due to our common interest in studying autism. While his lab was working on Fragile X syndrome, my lab has focused on understanding brain wiring abnormalities in another genetic cause of autism, Tuberous Sclerosis Complex.

Bear has discovered a particular way that the brain rewires and changes its configuration of synapses, or points of connection between neurons, in response to experience. Just like cars, synapses need both a gas pedal and a brake. The gas pedal is the strengthening (potentiation) of the synapse, while the brake is weakening (depression) of the synapse. If either the gas pedal or the brake is not working, the synapse doesn’t function properly. Together, these faulty synapses cause the larger neural circuit to function abnormally.

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Drug trials for fragile X syndrome lead the way for autism therapies

Randi Hagerman, Sfari.org |

A number of targeted trials on drugs that have the potential to reverse many of the behavioral and cognitive features of fragile X syndrome, are under way. Human and animal studies have shown that these medications can reverse many of the neurobiological and phenotypic features of fragile X syndrome. Along with these new trials, we will need accurate endpoints that can reliably measure the drugs’ effectiveness.

Fragile X syndrome is the most common inherited cause of intellectual disability and single-gene cause of autism. The full mutation has more than 200 repeats of a DNA sequence — CGG — at the front end of the FMR1 gene. This repeat number leads to a shutdown of the gene and a lack of the protein that it normally produces, fragile X mental retardation protein, or FMRP. The lack of FMRP causes fragile X syndrome and intellectual disability, in addition to autism, in 30 percent of individuals and pervasive developmental disorder-not otherwise specified in another 30 percent.

Between 55 and 200 repeats in the FMR1 gene causes what is called a premutation. The premutation leads to autism at a much lower rate — approximately ten percent of boys and less than two percent of girls.

The fragile X mutations cause autism through different molecular pathways. The absence or deficiency of FMRP affects the levels of many genes important for synaptic plasticity — how neurons strengthen important connections — and the outgrowth of neurites, the formation of new connections between neurons.

The fragile X premutation leads to higher levels of the RNA message for the FMR1 gene, which can bind to important proteins and dysregulate neuronal functions, leading to early cell death.

Promising trials:

Novartis and Roche both have an inhibitor of mGluR5, which activates a pathway that is overactive in those with fragile X syndrome.

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Top of the class

Virginia Hughes, Sfari.org |

‘Tis the season of graduations, even for autism drugs.

About a year ago, a small biotech company announced that one of its compounds improved social behaviors in a group of 15 children with fragile X syndrome. Last week, the drug matriculated to a phase-3 trial — the last and most difficult step on the long road to regulatory approval.

The drug, called arbaclofen or STX209, was developed by Seaside Therapeutics in Cambridge, Massachusetts. A decade ago, neuroscientist and Seaside founder Mark Bear had shown in mice that the cognitive problems of fragile X syndrome are caused by runaway glutamate, a common neurotransmitter.

STX209 acts on this pathway: it activates gamma-amino butyric acid type B (GABA-B) receptors, effectively putting the brakes on glutamate signaling.

In Seaside’s new trial, 120 individuals with fragile X will receive either STX209 or placebo for eight weeks. The company plans to enroll participants ranging in age from 12 to 25 years at 20 different clinics across the U.S.

Seaside is also investigating whether the drug can improve social problems of people who have autism but not fragile X syndrome. Many studies have implicated glutamate signaling and GABA-B glitches in people with autism.

Last fall, the company’s researchers reported that STX209 quells tantrums, irritability and social withdrawal in children with autism. That study was ‘open-label’: the participants’ doctors and parents knew they were taking the drug, making them susceptible to the placebo effect.

The company plans to launch a placebo-controlled trial of STX209 in autism this summer.

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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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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.

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By Madeline Drexler, hhmi.org |

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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.”

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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.
Forbes
New York Times
Bloomberg

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?

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Syndrome du X fragile : entrevue avec Pr. Vincent Desportes

Fondation Jérôme Lejeune |

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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.

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Syndrome du X fragile : étude clinique mondiale

Fondation Jérôme Lejeune |

À partir de février 2011, le dév. de l’AFQ056 passe en phase 3 avec la collaboration de 22 centres ds le monde, situés notamment aux USA, en Australie et dans de nombreux pays européens dont la France. Plus de 160 patients adultes seront concernés. À l’automne 2011, 1 étude portant sur des patients adolescents de 12 à 17 ans viendra compléter l’étude sur les adultes.

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Reported Rise in Autism Coincides with Rise in Autism Treatment Drugs

By BC Bass |

SAN NARCISO, Calif. — According to figures released by the Centers for Disease Control and Prevention (CDC), autism disorders have increased more than 60 percent over the last four years. Behavioral health scientist Catherine Rice, Ph.D., says it’s difficult to tell how much this data reflects actual increases in the disorder versus improvements in identifying conditions. Geraldine Dawson, Ph.D., the chief science officer for Autism Speaks, told WebMD, “Two decades ago, we were looking at a prevalence of one in 5,000 children. Now we’re looking at one in 100. That really is a staggering increase.”

But this dark cloud has a silver lining. Scientists think they may have identified the mutated chromosome responsible for causing the onset of the disorder. More importantly, and perhaps more presciently, pharmaceutical companies released an unprecedented number of drugs targeted at suppressing it, months before it was even discovered.

Fragile X
Mark Bear, who directs the Picower Institute for Learning and Memory at MIT, has discovered a system in the brain that could dramatically improve the quality of life for thousands of people with Fragile X.

Fragile X is a mutation on the X chromosome that can cause mental retardation and autism. Unlike the hotly debated Chemical X, which bestows superhuman abilities and the power of flight on prepubescent girls in undocumented studies, Fragile X appears to disrupt a system in the brain that regulates synapses — the connections between brain cells. Bear equated the condition to a car with missing breaks. Others have equated it to a marathon bong session at a Burning Man festival.

“Dire as it may seem, this news couldn’t have come at a better time,” said Quint Scroop, a senior lobbyist and moral champion from Pharmaceutical Research and Manufacturers of America (PhRMA), which has also lined up with a far-right Christian advocacy group to fight legislation supporting abortion-rights issues.

“Coincidentally enough,” Scroop continued, “the tremendous increase in the number of autism cases being diagnosed by doctors correlates directly to announcements by pharmaceutical companies that they have identified a vast array of drugs that can be used to treat autism. With so many of these doctors under contract with drug manufacturers, access to the medications is expedited. It’s really a win-win for autistics.”

New Drugs Winning the War
“I’ve always found the term ‘war on drugs’ quaint,” Scroop opined. “It means there’s a war and that drugs are winning. Well, there is a war — against this crippling disorder we call autism. There’s no reason why the people who suffer from it need to remain pariahs, throwing in their lots with other incurables. And, yes, the drugs will prevail.”

Scientists employed by leading pharmaceutical companies have indeed identified several drugs that seem to correct the problems inherent to Fragile X Syndrome. And they’re busy making even more. Cambridge, MA-based Seaside Therapeutics, for example, revealed that is has raised $30 million to pursue clinical trial development of new therapies for Fragile X and autism.

“Some of the most exciting developments with these drugs are the side benefits,” extolled a spokesperson for another leading drug producer. “In addition to curbing complications with Fragile X, our drugs are also proving to make children more docile and controllable. They stop toddler depression, abate restless leg syndrome, and even increase penis size.”

With the exception of commonplace side effects such as nausea, diarrhea, nose bleeds, suicidal thoughts, risk of stroke, irrational fear of water, and accelerated weight gain, the drugs are sure to succeed.

“We’re really pushing hard for legislation to enforce mandatory autism screening and treatments in the public schools,” boasted Scroop. “Parents should listen to and proactively follow the screening recommendations of our physicians, regardless of whether they have concerns.”

The proposed — and certain to pass — public testing and treatment program will be administered initially by only those doctors approved by the drugs’ manufacturers.

“It’s a safety thing,” Scroop explained.

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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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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.

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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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