Autism Speaks, Goals, Science, Sponsored Research Summary of Funded Studies, Dana Process

In January, Autism Speaks initiated a competitive grant process in conjunction with the Dana Foundation to stimulate new approaches to understanding, diagnosing and treating autism. Leading investigators from outside the field of autism science were encouraged to apply their ideas and expertise to autism, through a Request for Proposals (RFP) that was sent to all schools of medicine in the U.S. and to several select free-standing research institutions. New investigators, and those currently working on promising approaches in autism, also were invited to apply. Anticipating areas that were most likely to be represented by preliminary applicants, Dr. Gary Goldstein, Chairman of Autism Speaks Scientific Advisory Committee president and Dr. Guy M. McKhann, Director of the Johns Hopkins' Mind/Brain Institute, who is senior consultant to the Dana Foundation, asked leading experts in those fields to review proposals in their respective areas of expertise. Click here for a list of reviewers. A total of 57 preliminary applications were submitted in January of 2006 in response to the RFP. Reviewers recommended to Drs. Goldstein and McKhann that 30 of these applicants be invited to submit full proposals, and each of these applicants received invitations to submit full proposals, with instructions. All but two of these invited applicants (28 in total) submitted full proposals in April of this year. The five core reviewers each asked an additional one to three experts in their fields to assess the proposals, and the five core reviewers then submitted their comments, those of their co-reviewers, and their funding recommendations. The reviewers recommended 12 studies to the Autism Speaks' Board of Directors for funding consideration and approval. On June 13, all 12 studies were approved by the Autism Speaks Board of Directors. The 12 funded studies span efforts to explore the causes of autism, identify behavioral or biological markers that could be used to diagnose autism earlier, and identify or evaluate experimental therapies to treat autism and its symptoms. Many of the researchers are senior investigators in other fields, who now will apply their expertise and ideas to autism. Proposals were assigned to broad categories based on the primary research objectives and methodology. There are many proposals that involve multiple disciplines and approaches. To see a breakdown by broad topic areas, click the topic name in the list below: Genetics of Autism: 4 Studies Potential Early Diagnostic Markers: 4 studies Treatments: 4 Studies Studies exploring the genetics of autism University of North Carolina Patrick Sullivan, M.D. $100,000 over three years "Fragile X Syndrome" may yield clues to the genetics of autism It is well established that the risk of developing autistic behavior in greatly increased in Fragile X Syndrome, which occurs solely in males. While they have similar mutations in a gene called FMR1, symptom severity divides the affected males into three groups: those with mild, moderate and severe autism symptoms. The investigators, who are senior genetic psychiatric researchers, will use Fragile X Syndrome as a "toehold" into autism, conducting a pilot study that will provide the basis for applying to other funders for a larger-scale genetic study. They hypothesize that they can identify genes that predispose males with Fragile X Syndrome to autistic behavior. Aims of the pilot study are to: 1) Develop a sample of 150 males with Fragile X Syndrome; 2) Assess the degree of their autistic behavior; 3) Obtain DNA samples and establish the mutation status of the FMR1 gene; 4) Examine 768 genetic markers in 25 genes that they suspect are strong candidates for autism behaviors: and 5) Find statistical associations between the 25 genes' make-up and the degree of autism symptoms. If successful, they will have identified genes that predispose to autistic behavior in males with Fragile X Syndrome, setting the stage for a large-scale study of these genes in people with autism. Significance: The study of a small field of genes that are associated with autistic behaviors in males with this related disease could further pinpoint candidate genes that then could be efficiently studied in people with autism. Ultimately, this work could advance understanding of the genetic aspects of autism. Johns Hopkins University Andrew P.Feinberg, M.D., M.P.H.; and Stanford University Joachim F. Hallmayer, M.D., Ph.D. $100,000 over two years Exploring the "epigenetics" of twins with autism While scientists anticipate that genetics is involved in autism, no specific genes or gene interactions have been identified. In contrast, the field of "epigenetics," has provided important information about Rett syndrome, which has strong components of autism. Epigenetic alterations do not involve mutations in the sequences of DNA in genes. Rather, epigenetics concerns modifications that occur during cell division in "cytosine," one of the four "base pairs" of chemicals in DNA. The collaborating researchers, one of whom is expert in epigenetics, and the other in neurocognitive functioning in families, hypothesize that specific epigenetic alterations occur in autism. These alterations, they suspect, may affect disease incidence, and probably affect disease severity. The researchers will undertake epigenetic studies of DNA in blood samples from 30 pairs of monozygotic twins, who share the same DNA but have different levels of disease severity. They will look for epigenetic (chemical) changes in DNA that differ in the more severely affected, compared to less severely affected, twin in each pair. They then will confirm these chemical changes using a quantitative method for measuring them at the level of an individual gene. If they are able to identify specific epigenetic alterations that occur in autism, the research will open new avenues for diagnosis and treatment, such as identifying carriers of the epigenetic trait, prenatal testing, and devising new types of treatment for this inherently reversible chemical alteration. Additionally, since specific chemical alterations provide targets for environmental agents, the findings could lead to new ways to prevent or treat these interactions. Significance: If specific chemical alterations in DNA that occur during cell division are found to be associated with autism severity, and possible incidence of the disease as well, it could provide major new understanding of the basis for inheritance, and usher in new approaches to diagnosis and treatment and ultimately prevention of autism. Mount Sinai School of Medicine Jia Chen, Sc.D. $100,000 over one year Testing the "Extreme Male Brain" theory of autism Autism occurs four times more frequently in males compared to females, suggesting that a complex genetic predisposition, involving hormones, is involved. According to these researchers, since females have stronger emphasizing capability, while males have stronger systemizing capability, an "extreme male brain" (EMB) theory may explain the genetic basis of autism. This theory proposes that individuals along the autism spectrum are characterized by impairments in empathy alongside intact or even exceptional systematizing capacities. The researchers suggest that endogenous hormone levels of either or both the parent and the fetus during development are important. They hypothesize that inherited genetic variations in androgen metabolism modify the risk of autism, that there is a critical time when fetal exposure to androgens, specifically testosterone, is related to later development of autism spectrum disorder. They will test the EMB theory by undertaking genetic studies in 260 mother-child pairs in which the child has autism. First, the researchers will identify different forms of androgen-metabolizing genes that are biomarkers for integrated hormone levels. They then will assess this relationship between androgen metabolism and autism risk by analyzing forms of genes that favor the production and accumulation of testosterone. Thereafter, they will confirm whether the forms of genes identified occur in 300 healthy mother-child pairs, and whether maternal or fetal hormonal levels are key. Through this process, the researchers will derive direct evidence on whether or not the EMB theory is valid. Significance: If the EMB theory is validated, it would lead to further clinical efforts to assess genetic or individual susceptibility factors that increase the risk of autism, and to explore whether contributing hormonal, environmental or dietary exposures might be minimized. Cincinnati Children's Hospital Medical Center Marsha Wills-Karp, Ph.D., Cynthia M. Malloy M.D., and Patricia Manning-Courtney, M.D. $100,000 Does immune system dysfunction play a role in autism? Recent evidence suggests that the immune system, which normally protects the body against many diseases, may malfunction in people with autism and actually contribute to or produce this disorder. "Adaptive" immune "T" cells are summoned by ‘innate" immune cells to attack invaders. Immune T cells in some people, however, mistake the body's own tissues as foreign and attack them, a process called "autoimmunity." Immune T cells also can over-react to otherwise harmless substances, such as pollen, and produce allergies. Usually these potentially errant responses by immune T cells are kept under control by ‘regulatory T cells." Regulatory T cells are produced by the Foxp3 gene. According to the collaborating researchers, who combine expertise in autism, immunity, and patterns of disease ("epidemiology"), a disproportionate number of children with autism have immune system malfunctions that are similar to those seen in autoimmunity, allergy, or both conditions. They hypothesize that regulatory T cells in people with autism may be too few, or too weak, to provide a generalized ability to control errant immune responses, which contributes to, or causes, autism. The collaborators will study immune T cells, which circulate through the bloodstream, in blood samples taken from 20 children with autism and 20 healthy ("control") children. They will compare the number of regulatory T cells, and how effectively these cells control the "attacker" T cells, in blood samples from the two groups of children. The investigators also will find out whether differences exist in the two groups of blood samples in the amount of chemicals, called ‘cytokines," produced by attacking T cells. Excessive amounts of these cytokines, suggesting incomplete control of T cells by their regulators, may have consequences for the brain, providing a link between immune dysfunction and autism. Alternatively, some other factor may be common to both immune regulation and to autism. Significance: If this study indicates that a failure to properly regulate immune T cells is involved in autism, the research will provide a better understanding of immune system involvement in autism. The findings also may provide an immune "marker" to diagnose autism, and lead to development of specific immune-based therapies to prevent or treat autism. back to top

Studies Examining Potential Early Diagnostic Markers of Autism California Institute of Technology Ralph Adolphs, Ph.D. $100,000 over two years What is the biological basis of social deficits in people with autism? Problems that people with autism have in interacting with others are evident, but the biological reasons are not. This leading researcher of the roles of emotion and memory in social functioning is now exploring the biological basis of social dysfunction autism. He will collaborate with leading autism researchers to test the hypothesis that high functioning people with autism have impairments at the earliest stages of social processing, such as how they gaze at other people's faces, but that this impairment is influenced by alterations in higher cognitive processes, such as emotion or memory. The researchers will test this hypothesis by comparing how 10 highly functioning adults with autism, and 20 healthy adults, respond to faces. They will determine whether: 1) adults with autism have impaired abilities to process sensory information from faces; 2) these impairments correlate with altered higher cognitive processes that influence how they interpret information from faces; and 3) cognitive impairments increase in social situations, as participants move from viewing pictures of faces to looking at people, face-to-face. Sensory impairments will be measured by tacking participants' eye movements as they look at pictures of faces. Next, cognitive areas of the brain that influence visual processing will be identified, using functional magnetic resonance imaging (fMRI) while patients view the pictures. Then, the effects of social pressure on interactions between sensory and cognitive functions will be assessed by measuring changes in eye gazes that occur as participants move from viewing pictures of faces to interacting with another person via videoconference, to engaging in face-to-face interactions with another person. Significance: If eye gaze abnormalities related to social dysfunction are identified in highly functioning adults with autism, the findings could provide a tool for diagnosing autism in infancy. Moreover, by determining the biological bases for these difficulties in social interactions that are revealed by abnormal eye gazes, improved interventions might be developed and applied early in life. Yale University Katarzyna Chawarska, Ph.D. $100,000 over two years Why, and when, do children with autism develop difficulties recognizing faces? The skill to recognize faces is integral to social interactions, but it is a skill that children with autism either fail to develop or lose early in life. They tend to focus on the mouth rather than eyes, missing cues to emotions and to facial identification. This young researcher, newly working in a renowned Yale autism laboratory, will study toddlers to try to answer questions of when, and why, face recognition deficits occur in this population. Ultimately, the findings may provide new ways to diagnose autism earlier, and might also lead to earlier behavioral interventions. Acquiring typical face processing skills depends on experience. Healthy newborns' face discrimination skills evolve during infancy into a more refined focus, initially on the hairline and ears, and eventually on the eyes and mouth. School-aged children with autism (aged four), however, show abnormal patterns in responding to faces. When do the abnormalities develop, and do they involve problems with motivation, attention, learning or memory? The researcher hypothesizes that toddlers with autism have an impaired ability, prior to age two, to process human faces. Further, this impairment is related to abnormalities in the way they scan the face, and to attention problems that interfere with remembering faces. This hypothesis will be tested in a total of 75 toddlers, aged 18 to 24 months. Using eye tracking technology, the investigator will compare toddlers with autism to typically developing and developmentally delayed toddlers, on their selective attention to faces, their skills in recognizing previously seen faces, and whether or not they scan the face typically (from eye to the mouth, with little interest in hairline or ears). Significance: The research may improve understanding of the role of face perception in the development of autism symptoms. Moreover, if the research identifies face recognition problems that are present before age two, the findings could lead to earlier identification of infants at high risk of developing autism, and initiation of new types of treatment begun in infancy. University of California, San Diego Leslie J. Carver, Ph.D. $100,000 over three years Identifying early developmental signs associated with later development of autism An estimated 8 to 15 percent of younger siblings of children with autism are anticipated to be diagnosed with the disorder themselves by about age two. Yet little is known about early developmental processes that differentiate "at-risk" infants and toddlers who go on to develop autism from those who do not. The researchers hypothesize that early indicators of autism may be found in distinct but interrelated features of infants' developing brain systems during their first three years of development. Compared to typically developing infants and toddlers, the researchers suggest, infants who eventually develop autism show early differences in visual pathways which, in turn, lead to later-developing differences in their socially-relevant cognitive skills and their abilities to process emotions conveyed by facial expressions. This junior investigator in autism research will test her hypothesis in studies involving 75 "at-risk" younger siblings of children with autism, and 100 siblings of typically developing children. Participants will be enrolled at age six months, and followed up to age three. Initially, infants' visual pathways will be studied as they respond to luminance (black/white) versus chromatic (red/green) stimuli, and as they track random motion versus socially important motion. At ten months, the infants' visual pathways will be studied as they process objects compared to socially relevant faces. At 18 months, the toddlers' responses to emotional signals from others will be measured, as they are confronted with new toys that their parents respond to either positively or negatively. In these three studies of visual responses to ordinary and emotion-laden stimuli, the researchers will record the brain's electrical responses to events (called "event-related potentials"). These measures will be made using electroencephalography (EEG), which consists of placing small sensors on the scalp to record brain networks of electrical activity generated by responses to specific actions. By age three, participants who develop autism will be identified. The researchers then will, retrospectively, identify visual patterns that differed between those who developed autism compared to those who did not. Significance: If the study reveals that infants and toddlers who eventually develop autism have different patterns of visual system development, these differences could become diagnostic "markers" that could provide for early diagnosis. This could facilitate development and use of therapies that could begin early in the course of the disease. Duke University Helen L. Egger, M.D. and Adrian Angold, MRCP $100,000 over two years Identifying rates and effects of emotional and behavioral symptoms in children with autism Emotional and behavioral problems, like anxiety, mood disorders, disruptive behaviors, and irregular sleep and eating patterns, often accompany autism. If researchers better understood the nature and rates of occurrence of these problems, they should be able to manage the problems more effectively, and they also might be able to identify subgroups of children with similar problems whose autism has a similar course and severity. Subgroup identification would enable researchers to determine whether children in each subgroup have any common genetic factors associated with these patterns of the disease. The Duke University researchers previously developed an assessment tool that identifies effects and rates of behavioral and emotional problems in non-autistic children aged two through five. Now, the investigators will collaborate with autism researchers to adapt the current assessment tool to autism. The newly developed version of the tool will be evaluated in 100 participating parents of children with autism to determine the tool's reliability (its ability to repeatedly elicit the same person's response to the same question) and its validity (effectiveness, compared to less detailed measures currently used) to identify children's psychiatric problems. Based on the preliminary information derived, the researchers also will provide initial data on the nature and rates of co-existing behavioral and emotional problems in their autistic children. These rates will be compared to those obtained previously for non-autistic children. Through this process, the researchers will determine the utility of the new tool, and provide initial subgroup categorizations of the children for further studies. Significance: Developing a new tool to determine coexisting emotional and behavioral problems in children with autism is anticipated to lead to better interventions to manage these constellations of problems. The research also may lead to the identity of genes associated with subgroups of children with autism, based on their co-existing psychiatric problems. back to top

Testing Treatments for Autism and its Symptoms Penn State University Deborah C. Beidel, Ph.D. $100,000 over two years Adapting a comprehensive social skills training program to children with autism Social anxiety contributes to the difficulties that highly functioning children with autism or Asperger's syndrome have in interacting and forming relationships. While existing social skills interventions produce some benefit during training, the improvements do not carry over into the children's everyday interactions. In a preliminary study of four highly functioning children with autism who received "Social Effectiveness Therapy," however, the children made modest gains in their daily interactions. The therapy, developed by Penn State researchers who are leaders in studying social anxiety disorder, reinforces the children's formal training with home and community "practice" sessions involving parents and peers. The investigators hypothesize that, by modifying the therapy to enhance specific social skill deficits in children with autism, the children will show improved social skills, functioning, and decreased social anxiety. Twenty parents and their children, aged 8 through 12, will participate in a new 12-week "Comprehensive Social Skills Training for Children with Autism Spectrum Disorders" program. Weekly group sessions will focus on children's skill deficits, teaching them how to interact more effectively with peers and adults. Following each session, children will practice their skills with trained peers in social situations, such as bowling or pizza parties, and complete reinforcing "homework" assignments, under their parents' supervision, at home and in the community. Parents and peers receive training for their roles. The therapy's effectiveness will be assessed before and after training, through standardized ratings by parents, teachers, and clinicians, and from tests measuring the children's social skills. Results will be compared to a "control" group of children with autism who are on a waiting list for the program. Significance: This new social skills training model, if effective, could be implemented widely to improve social interactions in everyday settings by highly functioning children with autism. University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School James H. Millonig, Ph.D. $100,000 over three years Can stem cells be used to treat autism? Studies suggest that autism spectrum disorder (ASD) has a genetic and neuron-developmental basis. Evidence suggests that the brain's cerebellum is structurally abnormal in ASD. It has reduced numbers of "Purkinje" cells. Additionally, it is active in tasks, such as language and attention, which are abnormal in people with ASD. Two different DNA variants within the human gene called "ENGRAILED 2" (EN2) are often inherited in people with ASD, suggesting to the researchers that variants of this gene may confer susceptibility to ASD. The researchers have studied mice with the EN2 gene and found the mice to display autistic-like anatomical, neurochemical and behavioral defects, establishing it as a genetically relevant mouse model for ASD. They hypothesize that stem cells can reverse the damage created by autism-related variants of the EN2 gene in mice, replacing cerebellar cells lost to ASD, and can be used to treat some of the ASD symptoms. The researchers will first identify the stem cell source that has the greatest likelihood of being effective, and then determine the experimental conditions that will result in the most significant incorporation and differentiation of stem cells into brain cells affected by ASD. Thereafter, they will introduce these stem cells in the ASD mouse model, and determine their actions. Significance: this animal model stem cell research is anticipated to identify the source for stem cells that have the most likelihood of success in reversing ASD brain cell damage, and to provide initial evidence of whether stem cell therapy may be feasible in humans with ASD. Kennedy Krieger Institute Elaine Tierney, M.D. National institute of Child Health and Development Forbes D. Porter, M.D., Ph.D. $100,000 three years Testing the efficacy of simvastin on autism-related symptoms, and its effects on neurotransmitters Behavioral characteristics of autism, including irritability, social impairment, communication deficits and attention hyperactivity disorder, also occur in patients with mild forms of Smith-Lemli-Opitz syndrome (SLOS). This inherited disorder is caused by lack of an enzyme that converts 7-dehydrocholesterol (7-DHC) into cholesterol. When 7-DHC builds up after failing to convert to cholesterol, the build-up can be toxic. The drug simvastin impairs 7-DHC from being synthesized in the first place. It also may increase levels of the enzyme that can convert into cholesterol any 7-DHC that is produced. Can this drug, then, improve autism-like symptoms in patients with the mild form of SLOS? Can it provide clues to a potential role of cholesterol in autism spectrum disorders? One investigator's expertise in studying SLOS will be combined with the other investigator's expertise in conducting controlled clinical trials of simvastin. They will test the drug's efficacy in reducing autism-like behavioral symptoms, when given in conjunction with dietary cholesterol supplement, in 20 patients with mild SLOS who are between the ages of 4 and 18. They also will study whether simvastin, which can cross the blood-brain-barrier and enter the brain, increases cholesterol levels in the brain in a mouse model of SLOS, and in the human study participants. They hypothesize that symptomatic improvement will occur in response to increased levels of cholesterol in the brain, and that increased cholesterol will be associated with more normalized functioning of brain cells and neurotransmitters. Significance: The study will provide evidence of whether simvastin effectively reduces autism-like behavioral symptoms, as a potential treatment for children with autism spectrum disorders. The research also may reveal a potential role of cholesterol in these disorders. Vanderbilt University Beth A. Malow, M.D. $100,000 over two years Assessing the efficacy of melatonin in treating insomnia in children with autism Sleep disorders in children with autism can produce devastating stress on their families, and have been associated with the children's increased daytime hyperactivity and diminished attention. Parents of children with autism report encouraging results in helping their children fall asleep at night after giving them the dietary supplement melatonin. A naturally occurring neurotransmitter, melatonin has been shown to affect sleep/wake cycles when levels are low. While side effects of from using the melatonin dietary supplement appear to be few, no controlled clinical studies have been conducted to test its efficacy and determine optimum doses and time of administration. Doses used range from 1 to 10 mg, and the time that parents give it to their children range from hours to 30 minutes prior to bedtime. The researchers eventually plan to apply to other sources for funding for a large-scale randomized clinical trial to determine melatonin's efficacy, and in preparation for that they will conduct a pilot study to determine safety, optimum dose and time of administration. They will enroll 20 children with autism whose parents report on standardized tests that sleep disorders are a major problem. Prior to and after the clinical study of melatonin, parents will record their child's sleep patterns through "sleep diaries", their child's behavior, and parental stress levels. Then, parents will begin giving their child liquid flavored melatonin in gradually increased doses, from 1 mg. to a maximum tolerable level under 10 mg. Parents also will change, mi-way through the study, the time of giving melatonin from 30 minutes to five hours prior to their child's bedtime. Children will wear activity meters (watch-like devices) on their wrists that quantify movement and rest as a surrogate for wakefulness and sleep. Through the pilot study, the researchers will determine optimal dose, timing, and safety and tolerability of melatonin, and determine any needed modifications in the behavioral and stress scales to be used in the anticipated randomized clinical trial. Significance: This pilot clinical trial should establish the guidelines for undertaking a randomized clinical trial to determine whether dietary supplement melatonin effectively promotes sleep in children with autism-related insomnia, and reduces related parental stress. The results of the large-scale study, in turn, should improve medical management of autism-related insomnia. back to top

Reviewers Joe Coyle, M.D. – an expert in neuroscience and psychiatric research who is Director, Laboratory of Molecular and Psychiatric Neuroscience, McLean Hospital. David H. Ledbetter, Ph.D. – a leader in genetics research, who is Director of Medical Genetics, Emory University. Catherine Lord, Ph.D. – a renowned clinical psychology researcher specializing in development in children with autism spectrum disorders, and in development of diagnostic tools, who is Director, University of Michigan Autism and Communication Disorders Center. Jennifer Pinto-Martin, – Ph.D. –a highly regarded epidemiological researcher on patterns of the incidence and prevalence of autism in the population, who is Professor, University of Pennsylvania School of Nursing. Joseph Piven, M.D. – A leading researcher on the pathology of autism in the brain, genetic factors, and clinical approaches to treatment, who is Professor, Department of Psychiatry, University of North Carolina.