September 20, 2012

Investigative Compound Reduces Fragile X Symptoms In First Human Trials

Connie K. Ho for — Your Universe Online

Poor eye contact. Loss of language skills. These are just a few behavior attributes of individuals with autism spectrum disorder (ASD), according to the National Institute of Health. Scientists at the Rush University Medical Center and the University of California, Davis MIND Institute recently discovered that an investigational compound focusing on the main symptoms of fragile X syndrome is able to help treat social withdrawal. The finding is unique in that the compound could possibly be used to treat patients with ASD.

The results of the study were recently published online for the journal Science Translational Medicine.

"There are no FDA-approved treatments for fragile X syndrome, and the available options help secondary symptoms but do not effectively address the core impairments in fragile X syndrome," explained lead author Dr. Elizabeth Berry-Kravis, a professor of Pediatrics, Neurological Sciences, and Biochemistry at Rush University, in a prepared statement. "This is the first large-scale study that is based on the molecular understanding of fragile X syndrome and, importantly, suggests that the core symptoms may be amenable to pharmacologic treatment.”

The compound STX 209, also known as Arbaclofen, was included in the “first-in-patient” drug trial.

"This study shows that STX 209 is an important part of the treatment for fragile X syndrome, because it improved symptoms in those with significant social deficits or autism as well as fragile X syndrome," commented Dr. Randi Hagerman, medical director of the MIND Institute at UC Davis, in the statement. "Additional studies also are suggesting that STX 209 can be helpful for autism without fragile X syndrome. Until now, there have been no targeted treatments available for autism. This appears to be the first."

One of the most well-known single-gene causes of autism, fragile X syndrome causes intellectual impairment and social impairment. According to the U.S. Centers for Disease Control and Prevention (CDC), there are about 1 in 4,000 males and 1 in 6,000 to 8,000 females who display symptoms of social impairment. The organization also predicts that there are approximately 1 in 88 children born today who will be diagnosed with autism.

"This study will help to signal the beginning of a new era of targeted treatments for genetic disorders that have historically been regarded as beyond the reach of pharmacotherapy," noted Berry-Kravis in the statement. "It will be a model for treatment of autism, intellectual disability and developmental brain disorders based on understanding of dysfunction in brain pathways, as opposed to empiric treatment of symptoms. We hope mechanistically-based treatments like STX209 ultimately will be shown to improve cognitive functioning in longer-term trials."

By studying mice that were genetically engineered to display symptoms of fragile X, the scientists came to understand that behavioral issues in fragile X are due to the lack of neurotransmitter gamma-amino butyric acid (GABA). A drop in GABA has been seen in mice with fragile X and is believed to cause social anxiety or avoidance of others. In particular, Arbaclofen is effective in combining with a receptor on a synapse to cause a psychological reaction that would normally happen with a naturally occurring substance. The mice who were treated with arbaclofen displayed less social avoidance and repetitive behavior.

"In preclinical results, we demonstrate that STX209 treatment corrects core aspects of FXS pathophysiology in the fragile X mouse model, leading us to conclude that STX209 is a disease-modifying drug with the potential to significantly improve the lives of patients with fragile X," commented Dr. Randall Carpenter, president and chief executive officer of participating organization Seaside Therapeutics, in the statement. "STX209 could have a positive effect in this larger patient population."

The study with humans was the first of its kind and included 63 participants who ranged from six to 39 years of age. Between December 2008 and March 2010, 56 of the study subjects were included in the clinical trial and returned for an evaluation at two- and four-week intervals following treatment that spanned six weeks. The results of the medication were evaluated with the Aberrant Behavior Checklist, which looked at factors like irritability, lethargy/withdrawal, repetitive behavior and hyperactivity.

The findings showed that there was improvement for the participants and a lessening of problematic behaviors.

"There are currently no FDA approved therapeutics that address the core symptoms of fragile X syndrome, leaving patients and their caregivers with limited treatment options," replied Berry-Kravis in a statement. "We are very excited about the clinically meaningful improvements in social impairment observed to date in patients receiving STX209 – marking the first time a drug candidate has positively impacted a specific core symptom of fragile X. With continued success in ongoing clinical trials, I am hopeful that STX209 may be able to transform the treatment paradigm for fragile X syndrome – which would confirm what I have believed all along – that intellectual disability is not, as previously understood, an immutable condition."

The researchers plan to continue their study on STX 209, fragile X syndrome, and autism.

"We are looking forward to further studies utilizing STX 209 in both autism and fragile X syndrome because the fragile X mouse studies demonstrate long-term strengthening of synaptic connections with continued use of this medication," concluded Hagerman in the statement.