Autism Reversible?

Disorder of Neuronal Circuits in Autism Is Reversible, New Study Suggests

\t\t\t \t\t\t \t\t\t\tScienceDaily (Sep. 14, 2012) - People with autism suffer from a pervasive developmental disorder of the brain that becomes evident in early childhood. Peter Scheiffele and Kaspar Vogt, Professors at the Biozentrum of the University of Basel, have identified a specific dysfunction in neuronal circuits that is caused by autism. In the journal Science, the scientists also report about their success in reversing these neuronal changes. These findings are an important step in drug development for the treatment for autism.


According to current estimates, about one percent of all children develop an autistic spectrum disorder. Individuals with autism may exhibit impaired social behavior, rigid patterns of behavior and limited speech development. Autism is a hereditary developmental disorder of the brain. A central risk factor for the development of autism are numerous mutations in over 300 genes that have been identified, including the gene neuroligin-3, which is involved in the formation of synapses, the contact junction between nerve cells.
Loss of neuroligin-3 interferes with neuronal signal transmission
The consequences of neuroligin-3 loss can be studied in animal models. Mice lacking the gene for neuroligin-3 develop behavioral patterns reflecting important aspects observed in autism. In collaboration with Roche the research groups from the Biozentrum at the University of Basel have now identified a defect in synaptic signal transmission that interferes with the function and plasticity of the neuronal circuits. These negative effects are associated with increased production of a specific neuronal glutamate receptor, which modulates the signal transmission between neurons. An excess of these receptors inhibits the adaptation of the synaptic signal transmission during the learning process, thus disrupting the development and function of the brain in the long term.
Of major importance is the finding that the impaired development of the neuronal circuit in the brain is reversible. When the scientists reactivated the production of neuroligin-3 in the mice, the nerve cells scaled down the production of the glutamate receptors to a normal level and the structural defects in the brain typical for autism disappeared. Hence, these glutamate receptors could be a suitable pharmacological target in order to stop the developmental disorder autism or even reverse it.


Vision for the future: Medication for autism
Autism currently cannot be cured. At present, only the symptoms of the disorder can be alleviated through behavioral therapy and other treatment. A new approach to its treatment, however, has been uncovered through the results of this study. In one of the European Union supported projects, EU-AIMS, the research groups from the Biozentrum are working in collaboration with Roche and other partners in industry on applying glutamate receptor antagonists for the treatment of autism and hope, that in the future, this disorder can be treated successfully in both children and adults.

 

Medication Effective in Treating Social Withdrawal in Fragile X and Potentially Autism Patients

\t\t\t \t\t\t \t\t\t\tScienceDaily (Sep. 19, 2012) - An investigational compound that targets the core symptoms of fragile X syndrome is effective for addressing the social withdrawal and challenging behaviors characteristic of the condition, making it the first such discovery for fragile X syndrome and, potentially, the first for autism spectrum disorder, a study by researchers at Rush University Medical Center and the University of California, Davis MIND Institute has found.


The finding is the result of a clinical trial in adult and pediatric subjects with fragile X syndrome. It suggests, however, that the compound may have treatment implications for at least a portion of the growing population of individuals with autism spectrum disorder, as well as for those with other conditions defined by social deficits. The study is published online September 19 in 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," said Dr. Elizabeth Berry-Kravis, the lead author of the article. "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." Berry-Kravis is professor of Pediatrics, Neurological Sciences, and Biochemistry at Rush.


The "first-in-patient" drug trial was led by Berry-Kravis and Dr. Randi Hagerman of the UC Davis MIND Institute. It examined the effects of the compound STX 209, also known by the name Arbaclofen. The study was conducted collaboratively with Seaside Theraputics, a Cambridge, Mass., pharmaceutical company, that is focused on translating bench research on fragile X and autism into therapeutic interventions. Seaside Therapeutics produces the compound.


"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," said Hagerman, who is the medical director of the MIND Institute. "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."


Fragile X syndrome is the most common known cause of inherited intellectual impairment, formerly referred to as mental retardation, and the leading known single-gene cause of autism. Social impairment is one of the core deficits in both fragile X and autism. The U.S. Centers for Disease Control and Prevention (CDC) estimates that about 1 in 4,000 males and 1 in 6,000 to 8,000 females have the disorder. An estimated 1 in 88 children born today will be diagnosed with autism, according to the CDC.


"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," Berry-Kravis said. "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."


Studies in mice genetically engineered to exhibit features of fragile X, including social impairment, have suggested that the behavioral abnormalities in fragile X result from deficiencies in the neurotransmitter gamma-amino butyric acid (GABA). Decreased GABA has been observed in a mouse model of fragile X in many areas of the brain including the hippocampus, and has been hypothesized to be a basis of the social anxiety and avoidance characteristic of fragile X sufferers, the study says.
Arbaclofen is an agonist for gamma-amino butyric acid type B, or GABA-B, receptors. An agonist is a chemical that effectively combines with a receptor on a synapse to effect a physiologic reaction typical of a naturally occurring substance. Anxiety-driven repetitive behavior and social avoidance have been reduced in fragile X-engineered mice treated with arbaclofen. The current, first-of-its-kind study investigated whether Arbaclofen would produce similar results in human subjects.
The double-blind, placebo-controlled clinical trial initially recruited 63 subjects at 12 sites across the United States for the research, conducted between December 2008 and March 2010. The participants ranged in age from 6 to 39 years. Of the initial participants, 56 completed the clinical trial. There were no withdrawals related to drug tolerability. The majority of the subjects were treated with what was assessed as the optimum tolerated dosage of the study drug, 10 milligrams twice a day in younger patients and three times a day in adults. Compliance was monitored by patient guardians, who filled out a dosing form on a daily basis.


The study subjects returned for evaluations at two- and four-week intervals after beginning the six-week-long treatment. The drug then was tapered down over a one- to two-week period. After a week, the subjects entered a second treatment period.


The effects of the medication were scored on variables of the Aberrant Behavior Checklist, a behavior-rating scale for the assessment of drug-treatment effects. The checklist includes variables for irritability, lethargy/withdrawal, stereotypic (repetitive) behavior and hyperactivity, among other factors.
The study found improvement for the full study population on the social-avoidance subscale, an analysis validated by secondary ratings from parent observation of improvement in subjects' three most problematic behaviors. It found that the medication was the same as placebo, however, on the subscale for irritability.