Drug Treatment Corrects Autism Symptoms in Mouse Model
Autism results from abnormal cell communication. Testing a new theory, researchers at the University of California, San Diego School of Medicine have used a newly discovered function of an old drug to restore cell communications in a mouse model of autism, reversing symptoms of the devastating disorder.
The findings are published in the March 13, 2013 issue of the journal PLOS ONE.
“Our (cell danger) theory suggests that autism happens because cells get stuck in a defensive metabolic mode and fail to talk to each other normally, which can interfere with brain development and function,” said Robert Naviaux, MD, PhD, professor of medicine and co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego. “We used a class of drugs that has been around for almost a century to treat other diseases to block the ‘danger’ signal in a mouse model, allowing cells to return to normal metabolism and restore cell communication.”
“Of course, correcting abnormalities in a mouse is a long way from a cure for humans,” said Naviaux, “but we are encouraged enough to test this approach in a small clinical trial of children with autism spectrum disorder in the coming year. This trial is still in the early stages of development. We think this approach – called antipurinergic therapy or APT – offers a fresh and exciting new path that could lead to development of a new class of drugs to treat autism.”
Autism spectrum disorders (ASDs) are complex disorders defined by abnormalities in the development of language, social and repetitive behaviors. Hundreds of different genetic and environment factors are known to confer risk. In this study, nearly a dozen UC San Diego scientists from different disciplines collaborated to find a unifying mechanism that explains autism. Their work is the result of one of just three international “Trailblazer” awards given by the group Autism Speaks in 2011.
Describing a completely new theory for the origin and treatment of autism using APT, Naviaux and colleagues introduce the concept that a large majority of both genetic and environmental causes for autism act by producing a sustained cell danger response – the metabolic state underlying innate immunity and inflammation.
“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated,” Naviaux explained. “This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.”
Since mitochondria – the so-called “power plants” of the cell – play a central role in both infectious and non-infectious cellular stress, innate immunity and inflammation, Naviaux and colleagues searched for a signaling system in the body that was both linked to mitochondria and critical for innate immunity. They found it in extracellular nucleotides like adenosine triphosphate (ATP) and other mitokines – signaling molecules made by distressed mitochondria. These mitokines have separate metabolic functions outside of the cell where they bind to and regulate receptors present on every cell of the body. Fifteen types of purinergic receptors are known to be stimulated by these extracellular nucleotides, and the receptors are known to control a broad range of biological characteristics with relevance to autism.
The researchers tested suramin – a well-known inhibitor of purinergic signaling used medically for the treatment of African sleeping sickness since shortly after it was synthesized in 1916 – in mice. They found that this APT mediator corrected autism-like symptoms in the animal model, even if the treatment was started well after the onset of symptoms. The drug restored 17 types of multi-symptom abnormalities including normalizing brain synapse structure, cell-to-cell signaling, social behavior, motor coordination and normalizing mitochondrial metabolism.
“The striking effectiveness shown in this study using APT to ‘reprogram’ the cell danger response and reduce inflammation showcases an opportunity to develop a completely new class of anti-inflammatory drugs to treat autism and several other disorders,” Naviaux said.
Genomic “Hotspots” Offer Clues to Causes of Autism, Other Disorders
An international team, led by researchers from the University of California, San Diego School of Medicine, has discovered that “random” mutations in the genome are not quite so random after all. Their study, to be published in the journal Cell on December 21, shows that the DNA sequence in some regions of the human genome is quite volatile and can mutate ten times more frequently than the rest of the genome. Genes that are linked to autism and a variety of other disorders have a particularly strong tendency to mutate.
Clusters of mutations or “hotspots” are not unique to the autism genome but instead are an intrinsic characteristic of the human genome, according to principal investigator Jonathan Sebat, PhD, professor of psychiatry and cellular and molecule medicine, and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego.
“Our findings provide some insights into the underlying basis of autism—that, surprisingly, the genome is not shy about tinkering with its important genes” said Sebat. “To the contrary, disease-causing genes tend to be hypermutable.”
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Nutritional Supplement Offers Promise in Treatment of Unique Form of Autism
In mice, added amino acid reduced associated epilepsy, eased neurobehavioral symptom
An international team of researchers, led by scientists at the University of California, San Diego and Yale University schools of medicine, have identified a form of autism with epilepsy that may potentially be treatable with a common nutritional supplement.
The findings are published in the September 6, 2012 online issue of Science.
Roughly one-quarter of patients with autism also suffer from epilepsy, a brain disorder characterized by repeated seizures or convulsions over time. The causes of the epilepsy are multiple and largely unknown. Using a technique called exome sequencing, the UC San Diego and Yale scientists found that a gene mutation present in some patients with autism speeds up metabolism of certain amino acids. These patients also suffer from epileptic seizures. The discovery may help physicians diagnose this particular form of autism earlier and treat sooner.
The researchers focused on a specific type of amino acid known as branched chain amino acids or BCAAs. BCAAs are not produced naturally in the human body and must be acquired through diet. During periods of starvation, humans have evolved a means to turn off the metabolism of these amino acids. It is this ability to shut down that metabolic activity that researchers have found to be defective in some autism patients.
“It was very surprising to find mutations in a potentially treatable metabolic pathway specific for autism,” said senior author Joseph G. Gleeson, MD, professor in the UCSD Department of Neurosciences and Howard Hughes Medical Institute investigator. “What was most exciting was that the potential treatment is obvious and simple: Just give affected patients the naturally occurring amino acids their bodies lack.”
Gleeson and colleagues used the emerging technology of exome sequencing to study two closely related families that have children with autism spectrum disorder. These children also had a history of seizures or abnormal electrical brain wave activity, as well as a mutation in the gene that regulates BCAAs. In exome sequencing, researchers analyze all of the elements in the genome involved in making proteins.
In addition, the scientists examined cultured neural stem cells from these patients and found they behaved normally in the presence of BCAAs, suggesting the condition might be treatable with nutritional supplementation. They also studied a line of mice engineered with a mutation in the same gene, which showed the condition was both inducible by lowering the dietary intake of the BCAAs and reversible by raising the dietary intake. Mice treated with BCAA supplementation displayed improved neurobehavioral symptoms, reinforcing the idea that the approach could work in humans as well.
“Studying the animals was key to our discovery,” said first author Gaia Novarino, PhD, a staff scientist in Gleeson’s lab. “We found that the mice displayed a condition very similar to our patients, and also had spontaneous epileptic seizures, just like our patients. Once we found that we could treat the condition in mice, the pressing question was whether we could effectively treat our patients.”
Using a nutritional supplement purchased at a health food store at a specific dose, the scientists reported that they could correct BCAA levels in the study patients with no ill effect. The next step, said Gleeson, is to determine if the supplement helps reduce the symptoms of epilepsy and/or autism in humans.
“We think this work will establish a basis for future screening of all patients with autism and/or epilepsy for this or related genetic mutations, which could be an early predictor of the disease,” he said. “What we don’t know is how many patients with autism and/or epilepsy have mutations in this gene and could benefit from treatment, but we think it is an extremely rare condition.”
Sebat honored
Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at the UC San Diego School of Medicine has received the 2012 Roche and Nature Medicine Award for Translational Neuroscience. He was honored today at a symposium in Switzerland.
The award highlights young researchers who have made innovative and ground-breaking scientific discoveries in the field of translational neuroscience, especially related to autism spectrum disorders.
Sebat is being recognized for his work in better understanding the genetics of autism. Specifically, he, Michael Wigler of Cold Spring Harbor Laboratory and colleagues discovered that rare spontaneously occurring copy number variants are strongly associated with autism.
“This discovery was a key turning point in autism genetics and has now focused attention squarely on rare genetic variants, and spontaneous mutations in particular,” Sebat said.
Since the 2007 paper, researchers have made rapid progress in identifying individual mutations that confer high risk of disease, including autism.
Sebat, who is also chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases and a member of the Institute for Genomic Medicine, both at UC San Diego, has also made key discoveries in schizophrenia, including the fact that schizophrenia and autism share some of the same genes.
Gene Expression Abnormalities in Autism Identified
Genetic studies find dysregulation in pathways that govern development of the prefrontal cortex in young patients with autism
A study led by Eric Courchesne, PhD, director of the Autism Center of Excellence at the University of California, San Diego School of Medicine has, for the first time, identified in young autism patients genetic mechanisms involved in abnormal early brain development and overgrowth that occurs in the disorder. The findings suggest novel genetic and molecular targets that could lead to discoveries of new prevention strategies and treatment for the disorder.
The study to be published on March 22 in PLoS Genetics uncovered differences in gene expression between brain tissue from young (2 to14 years old) and adult individuals with autism syndrome disorder, providing important clues why brain growth and development is abnormal in this disorder.
Courchesne first identified the link between early brain overgrowth and autism in a landmark study published by the Journal of the American Medical Association (JAMA) in 2003. Next, he tested the possibility that brain overgrowth might result from an abnormal excess of brain cells. In November 2011, his study, also published in JAMA, discovered a 67 percent excess of brain cells in a major region of the brain, the prefrontal cortex – a part of the brain associated with social, communication and cognitive development.
“Our next step was to see whether there might be abnormalities of genetic functioning in that same region that might give us insight into why there are too many cells and why that specific region does not develop normally in autism,” said Courchesne.
In the new study, the researchers looked towards genes for answers, and showed that genetic mechanisms that normally regulate the number of cortical neurons are abnormal. “The genes that control the number of brain cells did not have the normal functional expression, and the level of gene expression that governs the pattern of neural organization across the prefrontal cortex is turned down. There are abnormal numbers and patterns of brain cells, and subsequently the pattern is disturbed,” Courchesne said. “This probably leads to too many brain cells in some locations, such as prefrontal cortex, but perhaps too few in other regions of cortex as well.”
In addition, the scientists discovered a turning down of the genetic mechanisms responsible for detecting DNA defects and correcting or removing affected cells during periods of rapid prenatal development.
Image using an electron microscope shows a cilium growing from a neuron. (Gleeson lab).
Scientists Link Evolved, Mutated Gene Module to Syndromic Autism
A team led by researchers at the University of California, San Diego School of Medicine reports that newly discovered mutations in an evolved assembly of genes cause Joubert syndrome, a form of syndromic autism.
Joubert syndrome is a rare, recessive brain condition characterized by malformation or underdevelopment of the cerebellum and brainstem. The disease is due specifically to alterations in cellular primary cilia – antenna-like structures found on most cells. The consequence is a range of distinct physical and cognitive disabilities, including poor muscle control, and mental retardation. Up to 40 percent of Joubert syndrome patients meet clinical criteria for autism, as well as other neurocognitive disorders, so it is considered a syndromic form of autism.
The cause or causes of Joubert syndrome are not well-understood. Researchers looked at mutations in the TMEM216 gene, which had previously been linked to the syndrome. However, only half of the expected Joubert syndrome patients exhibit TMEM216 gene mutations; the other half did not. Using genomic sequencing, the research team, led by Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, broadened their inquiry and discovered a second culprit: mutations in a neighboring gene called TMEM138.
“It is extraordinarily rare for two adjacent genes to cause the same human disease,” said Gleeson. “The mystery that emerged from this was whether these two adjacent, non-duplicated genes causing indistinguishable disease have functional connections at the gene or protein level.”
Dr. Karen Piece Discusses the Success of the 1-Year Well-Baby Check-Up Approach
The Autism Science Foundation interviews Karen Pierce, PhD on developing a screening for autism at a child’s one year “well baby” check-up:
Jonathan Carter spoke with Dr. Pierce about her work.
You’ve developed an early detection technique named the 1-Year Well-Baby Check-Up Approach. Can you describe how you developed the approach?
For me, the motivation was twofold and contained both clinical and research roots. First, I wanted to detect autism early to get kids into treatment as soon as possible. The second motivation was purely scientific. Autism is a neurobiological disorder, and if we want to make the big discoveries about what’s going on, we have to study the disorder while the symptoms are unfolding. So I needed to figure out a way to study autism as early as possible.
But then we are left with a problem: How do you study autism during the first year or two of life if a diagnosis doesn’t come until 2, 3 or even 4? So I decided the best way to address this issue is to implement a really simple, broadband screen.
Obviously symptoms of autism aren’t glaring over the first year of life. If they were, people would be diagnosing autism at that year of age. But, there are some signs that I thought would be caught by broadband screens. There is a really excellent broadband screen developed by Amy Wetherby and Barry Prizant, called the CSBS DP IT Checklist, but the screen had never been used as standard of care in a doctor’s office before. I started with my own pediatrician and asked her if she could spend a couple extra minutes during the one-year exam giving this screen to all of her patients. She tried it and it worked well, leading the other three doctors in her practice to do it. It all started with just four pediatricians. And it worked really well with those four, so I went out and started taking with other pediatricians around San Diego. By the time I hit 30 pediatricians word had spread far enough that I began to have pediatricians calling me asking to get into our program. Today over 170 pediatricians in San Diego are screening for autism and other delays at the 1-year check up using my program.
2011 Science Fellow Alysson Muotri spends his days using stem cells to understand autism, a disorder that affects 1% of all U.S. children. By examining the brain cells of adult patients with Rett syndrome specifically, he’s trying to determine if Autism Spectrum Disorder is permanent or if it’s possible to treat those cells with chemicals, inducing them to revert back to normal conditions. (via poptech)
Dr. Eric Courchesne explains how an over-abundance of neurons in the front cortex of the brain leads to autism. He recently published an important research paper revealing that children with autism have 67 percent more neurons in the frontal cortex. Courchesne explained that scientist must now work to discover why this overgrowth occurrs.
Autism Linked with Excess of Neurons in Prefrontal Cortex
A study by researchers at the University of California, San Diego Autism Center of Excellence shows that brain overgrowth in boys with autism involves an abnormal, excess number of neurons in areas of the brain associated with social, communication and cognitive development.
The scientists discovered a 67 percent excess of cortical cells – a type of brain cell only made before birth – in children with autism. The findings suggest that the disorder may arise from prenatal processes gone awry, according to lead researcher Eric Courchesne, PhD, professor of neurosciences at the UC San Diego School of Medicine and director of the Autism Center of Excellence.
Relying on meticulous, direct cell counting, the study – to be published November 9 by the Journal of the American Medical Society (JAMA) and funded in part by the National Institutes of Health – confirms a relatively recent theory about possible causes of autism.
