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social impairment—a core symptom of autism spectrum disorders—including symptoms such as preference to be alone, being withdrawn or isolated, and lack of social reactivity.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!
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.
At the International Fragile X conference held in Michigan last week, researchers working in partnership with Seaside Therapeutics presented promising results from a Phase II clinical trial with compound STX209. The research was presented by Elizabeth Berry-Kravis, MD, PhD, (Rush University Medical Center in Chicago, Illinois) and Randi Hagerman, MD, (M.I.N.D. Institute).
The study followed 63 patients with Fragile X from three groups spanning 6 to 40 years of age. The aim of the study was to investigate the safety and efficacy of STX209 across a broad range of individuals with Fragile X. The research team specifically looked at behavioral and cognitive measures that might indicate benefit from the drug. Indeed, they found statistically significant improvements in sociability in a pediatric group who had scored low on scales of sociability prior to the treatment. This result is particularly important because impairments in social function are a core feature of Fragile X, and also a core feature of autism spectrum disorders (ASD).
In a press release from Seaside Therapeutics, Dr. Hagerman offered a perspective on the results her team has observed. “A majority of the patients enrolled in the STX209 study are participating in the ongoing open-label extension study and are continuing to benefit from treatment with STX209,” said Dr. Hagerman. “Physicians and parents are reporting increased sociability and communication and decreased outbursts and tantrums. In several cases, patients have been successfully withdrawn from other medications, including mood stabilizers, anti-depressants and, most importantly, anti-psychotics—a significant benefit for patients given the severe side effects associated with this particular class of drug. It is my hope that, with further study, STX209 may be able to play a much needed role in improving the symptoms of fragile X syndrome and help patients and their families achieve an improved quality of life.”
These results are exciting for individuals and the families of those living with Fragile X. However, perhaps the greater excitement lies in what may come next. Fragile X is the most frequently observed genetic syndrome in individuals with ASD. Synaptic over-excitability has been observed in animal models of autism and is believed to be a common neurobiological underpinning. Seaside Therapeutics is currently exploring the potential for benefit in individuals with ASD through a clinical trial of STX209 in adults, adolescents and children with ASD. We anxiously wait for further data on the use of this compound.