080210xf's Blog

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

Archive for September, 2010

A new day dawning? First signs of promise for a drug that treats the core symptoms of autism

Autism Speaks Official Blog |

As many parents know, there currently are no available medical treatments for ASD targeting core autism symptoms.   Available medications target symptoms associated with ASD, such as hyperactivity, irritability, anxiety, or depression. Although the available medicines have helped many who struggle with the challenge of these symptoms, these drugs do not address the difficulties in the areas of social and communication deficits or repetitive behaviors and restricted interests.

Recently, hope has recently been kindled in a new drug for ASD that developed out of basic research on the neural mechanisms of Fragile X syndrome. Back in 2005 research in Dr. Mark Bear’s lab at Harvard showed the Fragile X mutation affects  communication between neurons.  Specifically, the mutation results in an excess of an excitatory neurotransmitter called glutamate, which impairs communication between neurons by making them over-stimulated.  Seeing the potential to help families, a small company called Seaside Therapeutics was started to see if certain drugs could help reduce the level of excitability of neurons.


Autism Radio UK will “benefit hundreds”


It’s claimed that a niche radio station dedicated to the subject of autism will benefit hundreds of people.

Autism Radio UK broadcasts from studios in North Staffordshire, and is believed to be the first project of its kind in the UK. The internet-based service is run and staffed by people who have links to autism or to Asperger syndrome.

Kevin Healey, whose idea the new station was, says it has a large Facebook following already.

The project has been funded by the Staffordshire Cares: Community Wellbeing Fund and the Access to Volunteering fund.


Studies tie fragile X syndrome to famous cancer pathway

Victoria Stern, Sfari.org |

A drug that interferes with a biochemical pathway important in cancer can reverse some brain defects in mouse models of fragile X syndrome, according to a study published 11 August in the Journal of Neuroscience.

Several genetic and animal studies in the past few years have linked the same pathway, called the phosphoinositide 3-kinase (PI3K) pathway, to autism.

The new report is one of the first to investigate the pathway’s role in fragile X syndrome, a genetic disease that leads to mental retardation and, in about one-third of cases, autism.

The findings suggest that glitches in PI3K could explain some of the overlap between the conditions, according to lead investigator Gary Bassell, professor of cell biology at Emory University in Atlanta.


Fragile X and autism: Intertwined at the molecular level leading to targeted treatments

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5’untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity.

Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA.

RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology.

There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations.

Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

Author: Randi HagermanGry HoemPaul Hagerman
Credits/Source: Molecular Autism 2010, 1:12 / via 7thspace.com

Tackling Fragile X Seaside’s unique funding stream enables progress in treatments for fragile X and autism

Lisa M. Jarvis, pubs.acs.org |

At the annual fragile X conference in Dearborn, Mich., in July, executives from Seaside Therapeutics found themselves confronted by a desperate mother. Her son was enrolled in a clinical study of STX209, a drug the small biotech firm is developing to treat the neurological disorder fragile X, and she had driven across several states to make a direct plea to the company: Please extend the trial, or at least provide medication to kids who participated.

“She didn’t know what she would do if it stopped,” recalls Seaside’s chief executive officer, Randy Carpenter. Indeed, preliminary results from the Phase II trial suggest the drug is having a positive effect on the behavior of kids with fragile X, which is caused by a mutation in a single gene and is also the most common known genetic cause of autism.

Seaside was able to convince the Food & Drug Administration to approve an open-label extension of the trial so that children could continue taking the drug. Nearly all of them have stayed on it. Like the mother at the conference, parents are in despair over the lack of treatments for fragile X, symptoms of which range from learning impairment to mental retardation.

Until recent interest by big pharma, Seaside was pretty much the only company developing drugs for fragile X and autism. Other small start-ups focusing on the diseases have one by one run out of money and closed up shop. Venture capitalists simply haven’t had an appetite to fund such risky drug development.

But Cambridge, Mass.-based Seaside has a secret weapon: an anonymous wealthy family that is committed to finding new treatments for fragile X and autism. With funds from the family and grants from the National Institutes of Health and patient advocacy organizations, Seaside has been able to explore the basic science of the brain disorders in tandem with its drug development efforts. Although unusual, that balanced approach to building up a scientific and clinical rationale looks like it’s working. In just five years, the firm’s two drug candidates have made it to mid-stage trials as a treatment for fragile X, where they show promise, and to early-stage tests on autism.


One drug, two birds


It’s been a year of big advances in the fragile X community: researchers better understand the role of the protein missing in the syndrome, pharma giants Novartis and Roche are developing new drugs for the disorder, and in July, biotech Seaside Therapeutics announced that one of its compounds, STX209, improves social behaviors in children with the syndrome.

The excitement has bled into the autism field, too, because of the possibility that these drugs could treat both disorders. Now there’s some data to back up that optimism. Yesterday, Seaside announced results from a phase II clinical trial showing that, in children with autism, STX209 lowers agitation, tantrums, irritability and social withdrawal.

STX209 (also called arbaclofen) stimulates gamma-amino butyric acid type B (GABA-B) receptors, which in turn dampen the excitatory signals that run unchecked in fragile X syndrome. Defects in GABA-B receptors have also been linked to autism.


Seaside Therapeutics to move autism drug to Phase 3 trials

Masshightech.com, By Julie M. Donnelly |

Seaside Therapeutics Inc. has issued positive results for a second Phase 2 clinical trial on its drug candidate to treat autism.

While the first study focused on fragile X syndrome, the most common cause of autism, the second study expanded the indication to a variety of autism spectrum disorders. The company has decided to move forward with Phase 3 trials for the potential therapy, called STX209, in both indications. The Cambridge-based biotechnology company said that the study showed a marked improvement in patients’ symptoms, including irritability and social withdrawal.

“These study results add to a growing body of evidence supporting the potential of STX209 to play an important role in treating neurodevelopment disorders such as fragile X syndrome and autism spectrum disorders,” said Randall L. Carpenter, CEO of Seaside Therapeutics, in a statement. “In addition, we have now observed significant improvement in social interaction across two studies. We believe the reduction in social withdrawal is important as it suggests that STX209 is demonstrating efficacy for a core symptom of both fragile X syndrome and autism.”


Seaside Therapeutics Reports Positive Data from Phase 2 Study of STX209 in Autism Spectrum Disorders

–Study of STX209 to advance in autism spectrum disorders–

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Sep 9, 2010 – Seaside Therapeutics, Inc. announced today positive data from an open-label Phase 2 study of STX209 conducted in patients with autism spectrum disorders (ASD). The primary endpoint of the study, an improvement on the Irritability subscale of the Aberrant Behavior Checklist (ABC-I), achieved statistical significance (p<0.001). In addition, STX209 demonstrated statistically significant improvements across a number of other global and specific neurobehavioral outcomes, including improvements on the Social Withdrawal subscale of the Aberrant Behavior Checklist (ABC-SW, p<0.001), which assesses a core symptom of ASD. A significant number of patients enrolled in the study are participating in an open-label extension study. STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist being studied for the treatment of ASD and fragile X syndrome (FXS). In July 2010, Seaside reported clinically meaningful data from a randomized, placebo-controlled study of STX209 in individuals with FXS. The Company intends to present the full results from both studies at future medical meetings.


Seaside advances autism drug

Boston Business Journal – by Julie M. Donnelly|

Seaside Therapeutics has issued positive results for a second phase 2 clinical trial on its drug candidate to treat autism.

While the first study focused on fragile X syndrome, the most common cause of autism, the second study expanded the indication to a variety of autism spectrum disorders. The company has decided to move forward with phase 3 trials for the potential therapy, called STX209, in both indications. The Cambridge-based biotechnology company said that the study showed a marked improvement in patients’ symptoms, including irritability and social withdrawal.

“These study results add to a growing body of evidence supporting the potential of STX209 to play an important role in treating neurodevelopment disorders such as fragile X syndrome and autism spectrum disorders,” Dr. Randall L. Carpenter, Chief Executive Officer of Seaside Therapeutics, said in a statement. “In addition, we have now observed significant improvement in social interaction across two studies. We believe the reduction in social withdrawal is important as it suggests that STX209 is demonstrating efficacy for a core symptom of both fragile X syndrome and autism.”

The second trial for the broader therapeutic indication was conducted as a so-called open label study, which means there was no control group taking a placebo. This type of study is considered to be less scientifically rigorous. The first study, focusing on fragile X, was a placebo-controlled study.

Thirty-two patients with autism spectrum disorders between the ages of 6 and 17 were enrolled in the study. Two patients withdrew from the study due to a worsening of their symptoms. Another patient reported a serious adverse event, a worsening of aggression, as the patient transitioned off the drug.

Read more: Seaside advances autism drug – Boston Business Journal

Santhera, Ipsen Sign $181M Collaboration for Fipamezole

By Cormac Sheridan,  BioWorld International Correspondent |

… Others pursuing that indication include Addex Pharmaceuticals SA, of Geneva, which is moving ADX48621, a negative allosteric modulator of metabotropic glutamate receptor 5, into a Phase II trial later this year. Basel, Switzerland-based Novartis AG began a Phase IIb trial of AFQ056, which acts on the same target, late last year. It said earlier this year that it planned to file for approval in 2012.


Autism Moms Have Stress Similar To Combat Soldiers

Michelle Diament, Disability Scoop |

Mothers of adolescents and adults with autism experience chronic stress comparable to combat soldiers and struggle with frequent fatigue and work interruptions, new research finds. These moms also spend significantly more time caregiving than moms of those without disabilities.

Researchers followed a group of moms of adolescents and adults with autism for eight days in a row. Moms were interviewed at the end of each day about their experiences and on four of the days researchers measured the moms’ hormone levels to assess their stress.

They found that a hormone associated with stress was extremely low, consistent with people experiencing chronic stress such as soldiers in combat, the researchers report in one of two studies published in the Journal of Autism and Developmental Disorders.

“This is the physiological residue of daily stress,” says Marsha Mailick Seltzer, a researcher at the University of Wisconsin-Madison who authored the studies. “The mothers of children with high levels of behavior problems have the most pronounced physiological profile of chronic stress, but the long-term effect on their physical health is not yet known.”



Qu’en est-il des pères? / What about dads?

Drug appears to aid children with fragile X syndrome

Phyllis Brown, UC Davis |

SACRAMENTO — One of the antibiotics most commonly prescribed to treat adolescent acne can increase attention spans and communication and decrease anxiety in patients with fragile X syndrome, the most common inherited cause of mental impairment, according to a new survey study that is the first published on parents’ reports of their children’s responses to treatment with the medication.

Led by researchers at the UC Davis MIND Institute, the study examined parents’ observations of their children’s responses to minocycline — not the efficacy of treating patients with the drug. However, the researchers said that the study results are extremely promising. They led to a placebo-controlled clinical trial of treating people with fragile X with minocycline, funded by the National Fragile X Foundation.

“Minocycline Treatment in Patients with Fragile X Syndrome and Exploration of Outcome Measures” is published in the September 2010 issue of the American Journal of Intellectual and Developmental Disabilities. In the study, parents relate that after being treated for an average of three months, their children showed improvements in their use of language, attention levels and behavior, while experiencing mostly mild side effects.

“This preliminary survey demonstrated improvements in participants, however, a controlled clinical trial is needed to compare the efficacy of treating patients with minocycline to treatment with a placebo,” said Randi Hagerman, Fragile X Endowed Chair, medical director of the UC Davis MIND Institute and one of the world’s leading experts on fragile X syndrome.

Fragile X syndrome is a genetic disorder, 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.


Studies explore amygdala problems in fragile X syndrome

Kelly Rae Chi, SFARI |

The amygdala, a brain region that regulates fear and anxiety, shows abnormal neuronal signaling in a mouse model of fragile X syndrome, according to two studies published this summer.

Previous imaging studies in people and behavioral experiments in mice have implicated the amygdala in the syndrome. The new studies are the first to explore cellular defects in the region in fragile X.

In particular, they reveal that mouse models of fragile X — the most common inherited form of mental retardation and autism — seem to have specific differences in the ways their amygdalae and hippocampi behave.

Much of the research on brain dysfunction in fragile X has focused on the hippocampus, a region that processes learning and memory.

Drugs touted as potential therapies for fragile X also appear to be more effective at reversing some of the abnormalities associated with the syndrome in the hippocampus than in the amygdala.


Children’s National Researchers Unlock a Key Cause of Fragile X Syndrome

HealthCanal.com |

Findings May Have Implications for Autism Spectrum Disorders

Washington, DC — Researchers with the Center for Neuroscience Research at Children’s National Medical Center have identified a brain defect responsible for many of the social and emotional problems associated with Fragile X Syndrome (FXS). Specifically, the investigators uncovered that neuronal inhibitory neurotransmission, a major form of communication in the brain, is significantly diminished in the animal model of FXS. FXS is the most common inherited cause of mental retardation and the leading known genetic cause of autism as one-third of people with FXS also have autism spectrum disorders.

In addition to this discovery, in slice cultures the team also demonstrated the effectiveness of a drug that may correct the defect, which may inform the development of therapies for FXS and other autism spectrum disorders. The next step is to collaborate with clinical researchers to test the drug more broadly for safety and efficacy. According to Children’s National researchers and other studies, the national and international neuroscience research community is exploring how best to take that next step.

The discoveries resulted from the three-year collaboration of two laboratories at Children’s National and a Kennedy Krieger-Johns Hopkins laboratory. One laboratory, led by Joshua Corbin, PhD, co-principal investigator, works to understand the basic mechanisms of development of the amygdale—a specific part of the brain intimately involved in behavioral deficits in autism spectrum disorders. The other laboratory, led by Molly Huntsman, PhD, co-principal investigator, studies how neurotransmitters that are responsible for inhibitory and excitatory behavior work for proper communication in the brain.


Parents of fragile X kids report improvements with antibiotic minocycline

Los Angeles Times |

Parents of children with fragile X syndrome reported improvements in their children’s attention spans and communication skills as well as decreased anxiety after the children were given the antibiotic minocycline, researchers said Tuesday. The results were strictly observational and were uncontrolled, but they suggest the drug — which is already used widely for treating teen acne — might also have a use for the fragile X condition. The results were sufficiently promising that the National Fragile X Foundation is now sponsoring a preliminary clinical trial.

Fragile X is a genetic disorder caused by defects on the X chromosome, one of the cell’s two sex chromosomes. It affects about one in 3,600 males and one in 4,000 females in the United States, causing a variety of disabilities that include learning disorders, intellectual impairment and behavioral and emotional problems. It is also associated with certain physical traits, such as prominent ears and unusually flexible finger joints. Symptoms are typically more severe in boys than in girls.