080210xf's Blog

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

Archive for June, 2011

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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The next step toward treatment for the core symptoms of autism

Blog.autismspeaks.org, by Chief Science Officer of Autism Speaks, Geraldine Dawson, Ph.D.

I often get the question: How is the research we are funding on single gene disorders, such as Fragile X, relevant to the larger population of individuals with ASD? My answer is that, although autism has many different causes – including single gene mutations, multiple genetic factors, and even environmental factors – it is likely that these causes affect common underlying biological pathways. By studying the “simpler” single gene disorders, especially by studying animal models of these disorders, we can discover these pathways and develop medications that hopefully can help restore the functioning of these pathways.

As you will see in the press release, this strategy is being implemented by Seaside Therapeutics. With the help of funding from Autism Speaks and NIH, Mark Bear and other scientists developed an animal model for Fragile X and discovered that glutamate, an excitatory neurotransmitter, is affected by the Fragile X mutation. An overabundance of glutamate is interfering with the ability of neurons to communicate with each other (synaptic functioning). SeasideTherapeutics then tested a medicine, STX209 (arbaclofen), which helps to restore normal synaptic functioning, in a clinical trial with people with Fragile X. They found encouraging results! The next step, which was launched yesterday, is to test the efficacy of STX209 in individuals with ASD. The hope is that this medicine will improve social behavior and reduce irritability (e.g. aggression, tantrums) in people with ASD.

In the press release Randall L. Carpenter, M.D., President and Chief Executive Officer of Seaside Therapeutics says, “In our open-label Phase 2a study of STX209, we observed significant improvements in social impairment—a core symptom of autism spectrum disorders—including symptoms such as preference to be alone, being withdrawn or isolated, and lack of social reactivity. We are spearheading late-stage development of a drug candidate that has the potential to change the treatment paradigm for autism spectrum disorders—addressing core symptoms—and are truly excited about the prospect of helping patients and their families achieve an improved quality of life.”

Arbaclofen acts by stimulating the release of GABA in the brain. To make an simplified analogy, if we think of glutamate as the accelerator pedal in brain, then GABA is the brake pedal. By reducing glutamate through stimulating GABA receptors, the first clinical trial with people who have Fragile X syndrome demonstrated positive effects on behavior.

In Phase 2b of the trial, 25 sites will conduct a randomized, placebo-controlled trial of arbaclofen, enrolling 150 people with ASD for a total duration of treatment of 12 weeks. For more information about the clinical trial visit http://www.clinicaltrials.gov .

We will be sure to keep you informed as this study and other translational research progresses!

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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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Fragile X protein acts as toggle switch in brain cells

Shared.web.emory.edu |

New research shows how the protein missing in fragile X syndrome – the most common inherited form of intellectual disability – acts as a molecular toggle switch in brain cells.

The fragile X protein, called FMRP, hooks up with a group of molecules called microRNAs to switch the production of other proteins on and off in response to chemical signals, scientists at Emory University School of Medicine have discovered.

The results appear in the June 10 issue of Molecular Cell.

“For learning and memory to take place, neurons need to be able to make new proteins on demand, at particular synapses in a localized way,” says senior author Gary Bassell PhD, professor of cell biology and neurology at Emory University School of Medicine. “It appears that FMRP has evolved to use microRNAs to control the synthesis of proteins at synapses.”

The research team included the first author, Ravi Muddashetty PhD, and contributing co-authors, Vijayalaxmi Nalavadi PhD, Christina Gross PhD, Xiaodi Yao, Oscar Laur PhD and Lei Xing PhD. This research was done in collaboration with Stephen Warren PhD, professor and chair of the Department of Human Genetics.

In fragile X syndrome, FMRP’s absence leads to overactive signaling and unregulated protein production at synapses, the junctions between brain cells where chemical communication occurs. This leads to structural changes at synapses and an impairment of cells’ ability to respond to chemical signals, which in turn interferes with learning and memory.

Muddashetty and Bassell focused on a particular protein called PSD-95, whose production they had previously discovered was regulated by FMRP – although they didn’t know how FMRP exerted its control. PSD-95 appears to have an important role in anchoring together signaling molecules at synapses, the parts of neurons directly involved in learning and memory. Mice lacking the gene for PSD-95 develop normally but have more difficulty learning the location of a hidden platform in a water maze, compared with normal mice.

“The changes at synapses seen in fragile X syndrome are probably not caused by the overproduction of a single protein,” Bassell says. “But we think that losing the ability to make PSD-95 on demand is an important component.”

In cultured neurons, Muddashetty studied part of the RNA molecule encoding PSD-95, which responds to excitement by the neurotransmitter glutamate. This way he could dissect which proteins and RNA molecules were needed. Interfering with a particular microRNA, called miR-125, could stop the PSD-95 RNA from responding to glutamate signaling and could even drive neurons to produce more protrusions at their synapses.

MicroRNAs are involved in a process called RNA interference, whose discovery earned the 2006 Nobel Prize in Medicine. RNA interference is a way that short RNA molecules (microRNAs) can silence a stretch of genetic code.

These tiny RNA molecules have become a widely used laboratory tool for shutting off a specific gene. When the RNA molecules are introduced into the cell, they are actually hijacking a machine inside the cell called RISC (RNA-induced silencing complex). MicroRNAs normally govern the activity of RISC, which can prevent a given gene from being translated from RNA into protein.

In a sense, FMRP is acting as a “RISC manager.” Together with microRNA, it clamps down on an RNA, preventing the synthesis of protein, until glutamate signals force them to loosen up. Thus, FMRP determines when the protein should be made at the synapses.

“Future work may uncover whether this is a general mechanism to guide specific miRNAs onto target mRNAs at synapses,” the authors write.

The finding illustrates how microRNAs are emerging as key players in neurological development and disease, Bassell says. Since a given microRNA can regulate hundreds of targets, one potential drug strategy for fragile X syndrome would be to aim at restoring microRNA function.

The research was supported by the National Institutes of Health, the Fraxa Research Foundation and National Fragile X Foundation.

Reference:

R.S. Muddashetty, V.C. Nalavadi, C. Gross, Xiaodi Yao, L. Xing, O. Laur, S.T. Warren; and G. Bassell. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation and mGluR signaling. Mol. Cell (2011).

Writer: Quinn Eastman

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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