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social impairment—a core symptom of autism spectrum disorders—including symptoms such as preference to be alone, being withdrawn or isolated, and lack of social reactivity.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 www.clinicaltrials.gov .
We will be sure to keep you informed as this study and other translational research progresses!
Nancy Jones, Ph.D., Director of the Autism Treatment Network and Clinical Trials Network
In one of the final sessions at IMFAR, several presentations provided updates in three important areas of intervention and treatment research.
Using technology to make interventions more accessible
Laurie Vismara, Ph.D. from UC Davis, MIND Institute reported on a new approach to make training for families on the Early Start Denver Model (ESDM) more accessible. Typically, families and clinicians attend training and coaching sessions in person at the clinic. Using web and DVD technology, Dr. Vismara and her colleagues have developed a program where families use web-based video conferencing for training sessions with a therapist. Families also had access to an interactive DVD including modules covered in training sessions that provide summaries of the key sessions, video examples, supportive videos, and feedback exercises. The study examined how this new web-based approach compared to in-person sessions. In a small pilot group of ten families, the researchers found that parents’ ability to implement the activities from the intervention was comparable to that found in families trained in-person. Improvement in the children’s word production and imitation skills were also comparable to children whose families had in-person ESDM sessions. A manual of this web-based approach is currently being developed. This approach holds promise to make interventions accessible to more families and to ensure children get timely intervention of the appropriate intensity.
Effectiveness of melatonin for sleep disorders in ASD
Many families and individuals with ASD report sleep problems. To alleviate these sleep problems, some individuals use melatonin, a hormone that is readily available and sold over-the-counter as a supplement. But despite melatonin’s easy accessibility and wide-spread use, there are not a large number of systematic studies of its use for sleep disorders in ASD.
Beth Malow, M.D., a neurologist and sleep specialist, and her team at Vanderbilt University Medical Center (VUCM), reported results from a pilot open-label study of melatonin for improving sleep onset. Many children suffer from sleep onset insomnia, which is a delay in their ability to fall asleep. The study examined the effectiveness of using melatonin to help children (ages 3-10) who have difficulty falling asleep (more than 30 minutes delay on more than three days a week). In addition to the melatonin, all families also were provided with sleep education on how to improve sleep. Twenty-four of the twenty-five children in the study showed an improvement at moderate doses that were well tolerated, decreasing the time it took them to fall asleep on more than three days a week. This study was an open label study, which means that families were aware of the treatment they were receiving. This study provides initial evidence for the potential effectiveness and safety of the treatment and also preliminary information to guide development of a planned multi-site, randomized controlled trial of melatonin.
Arbaclofen shows potential to treat social and communication problems in ASD children with high irritability
In a previous clinical trial on individuals with Fragile X, arbaclofen was found to lessen children’s tendency to withdraw socially and improved social behavior. The study reported at IMFAR examined the effectiveness of arbaclofen in improving social and communication skills in children with ASD. The children were 6-17 years of age, had a diagnosis of autism or PDD-NOS and also had high levels of irritability. The study was an 8-week, open-label study. Craig Erikson, M.D., of Indiana University School of Medicine reported the findings of the multi-site trial. Key improvements were noted for irritability, social withdrawal and communication. A double-blind, placebo-controlled trial is planned to begin early in 2011.
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.
The drug, arbaclofen, is the first drug being tested. Arbaclofen works by increasing GABA, an inhibitory transmitter, which counteracts the over-excitability of cells. The preliminary results of a trial conducted with children with Fragile X syndrome looked so promising that Seaside Therapeutics announced the results on this year’s meeting of the International Society for Autism Research (read a review of that meeting’s highlights). More recently, arbaclofen has been tested in children with ASD without Fragile X. The results of this trial have been reported in the news. The trial treated 25 children and adolescents with autism for 8 weeks and the preliminary data revealed that arbaclofen was not only well-tolerated but also increase sociability and eye contact, and reduced tantrums and anxiety.
Of course, the testing of this drug continues and a review of the data by independent scientists is essential for evaluating the true benefit of this new drug, however these preliminary results offer good reason for hope and that news is always worth sharing.