Individuals with autism display deficits in social interaction and restricted behaviors, and are at least three times more likely to experience chronic gastrointestinal (GI) symptoms than the general population.

Mutations in the Shank3 gene, which encodes a major scaffolding protein in the postsynaptic density of excitatory neurons, contribute to approximately 1% of ASD cases. The Shank3B-/- mouse is depleted in the major forms of SHANK3, resulting in behavioral phenotypes in mice that are similar to those observed in ASD. We show that Shank3B-/- mice display an increase in whole GI transit time (WGTT) and ex vivo colon migrating motor complexes involved in propulsive contractions, indicating altered GI motility compared to wild-type mice.

Following colonization with a gut microbiome derived from wild mice, Shank3B-/- mice exhibit pronounced anxiety phenotypes. Intriguingly, depletion of SHANK3 in adult neurons using AAV-mediated delivery of Cre-recombinase in Shank3flox4-22 mice results in decreased WGTT compared to controls.

Taken together, the data suggests complex gene x environment interactions impact behavior and GI comorbidities. As GI symptoms can impact quality of life, this research may lead to novel strategies to improve non-behavioral features of ASD.

Sarkis K Mazmanian, PhD, is the Luis & Nelly Soux Professor of Microbiology in the Division of Biology & Biological Engineering at the California Institute of Technology (Caltech). He is a Phi Beta Kappa graduate from the University of California, Los Angeles, where Dr. Mazmanian also received his PhD training in microbiology and immunology. He was a Helen Hay Whitney Postdoctoral Fellow and subsequently appointed assistant professor at Harvard Medical School in 2006, and later that year moved to Caltech.

Dr. Mazmanian has won numerous awards including a Searle Scholar, Young Investigator of the Year at Harvard Medical School, Damon Runyon Innovation Award, was named by Discover Magazine as one of the “Best Brains in Science under 40”, “Life Science Superstar” by Genetic Engineering and Biotechnology News, and recently received the MacArthur Foundation “Genius” award. His laboratory focuses on the study of beneficial bacterial molecules from the human gut microbiome as novel therapies for immunologic and neurologic disorders, with a specific focus on developing probiotic treatments for autism. He is a founder of 2 biotech companies, and has or currently serves on the Scientific Advisory Board of over a dozen companies, academic centers and not-for-profit foundations.

The effects of infection and inflammation on neurological disorders have previously been noted. For example, a subset of children with autism spectrum disorder (ASD) exhibit temporary but considerable improvements of their behavioral symptoms during episodes of fever, a sign of systemic inflammation.

However, a mechanistic understanding of how fever-associated immune responses translate into behavioral relief—both at the molecular and neural level—is lacking.

We show that the social behavioral deficits in offspring exposed to maternal immune activation can be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioral rescue was accompanied by a reduction in neural activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which has previously been implicated in the manifestation of behavioral phenotypes associated with offspring exposed to MIA. We also show that both the behavioral rescue and the reduction in neural activity is mediated through the expression of IL-17 receptor subunit a (IL-17Ra) in the neurons of the S1DZ.

These results suggest that inflammation can be harnessed to mitigate symptoms associated with neurodevelopmental disorders.

Jun Huh, Ph.D. is a Speaker at Department of Immunology Harvard Medical School. Dr. Huh obtained his PhD from the California Institute of Technology and conducted his postdoctoral work at NYU School of Medicine as a recipient of the Jane Coffin Childs Memorial Fund Fellowship. He received the NIH Pathway to Independence Award and the Smith Family Awards Program for Excellence in Biomedical Research. Dr. Huh was named a 2015 Searle Scholar and a 2016 Pew Scholar. In 2019, Dr. Huh was selected as an investigator in the Pathogenesis of Infectious Disease by the Burroughs Wellcome Fund.

Dr. Huh’s laboratory studies mechanisms by which maternal inflammation leads to neurodevelopmental disorders in offspring. In mice, pregnant females infected with viruses give birth to offspring that exhibit behavioral phenotypes that resemble the symptoms of autism spectrum disorder and/or schizophrenia. His lab has shown that the bacterial community in the maternal gut plays an essential role in this model by promoting the differentiation of Th17 cells. Dr. Huh is also interested in identifying host- and bacteria-derived factors that regulate inflammation in the mammalian gut.

A major challenge facing modern medicine is translating advances in genetics and genomics into a better understanding of disease mechanisms and trajectories and eventually patient care. This is especially evident in disorders such as autism, where over 100 risk genes have been identified. The mere number of genes and their heterogeneity challenges mechanistic studies.

We have used system biology approaches to ask whether ASD risk genes converge on specific pathways. Further, we have worked with colleagues to develop in vitro systems based on stem cells to study these pathways.

We propose that the genomic data from these studies may be used for unbiased drug screening based on gene expression.

Dr. Daniel Geschwind is the Gordon and Virginia MacDonald Distinguished Professor of neurology, psychiatry and human genetics at the UCLA School of Medicine, and the Senior Associate Dean and Associate Vice Chancellor of Precision Medicine at UCLA. Dr. Geschwind obtained his M.D./Ph.D (neurobiology) at Yale School of Medicine (AOA) and completed his internship, residency (Neurology), and postdoctoral fellowship at UCLA, joining the faculty in 1997. Dr. Geschwind’s laboratory takes a system biology approach, integrating genetic, genomic and bio-informatic approaches with basic neurobiological investigation in model systems and human brain.

The over-arching goal of these efforts is to develop new therapeutics for nervous system disorders for which disease-altering therapies are not currently available, including autism and neurodegenerative disorders. He serves on the editorial boards of several journals including Cell, Current Opinion in Genetics & Development, Neuron and Science and has published over 450 manuscripts. Dr. Geschwind is also a strong advocate for data and biomaterial sharing, having provided scientific oversight for the Autism Genetic Resource Exchange (AGRE), and is an elected member of the American Academy of Physicians and the National Academy of Medicine, USA.

Many people with autism experience gastrointestinal issues including diarrhoea, constipation, bloating, abdominal pain and vomiting, however the cause is unknown.

More than 150 gene mutations associated with autism subtly alter neuronal communication at synapses in the brain. Similarly, the autism-associated R451C mutation in the Neuroligin-3 gene alters brain function in mice. In addition to experiencing gastrointestinal problems, people with autism and their families are also more likely to be diagnosed with inflammatory disorders. Since it is established that the nervous system and immune cells are in constant bidirectional communication, changes in neuronal activity may also alter inflammatory responses.

The aim of this research was to identify if the R451C mutation in Neuroligin-3 causes gastrointestinal dysfunction in mice. Our findings demonstrates that the autism-associated R451C missense mutation in Neuroligin-3 alters the structure and function of the enteric nervous system and causes gastrointestinal dysfunction in mice. These mice also show changes in both the gut microbiome and in immune cells, suggesting that this mutation impairs inflammation pathways.

This research indicates that autism-associated gene mutations affecting brain function can also impact the gut, and likely cause gastrointestinal dysfunction in some individuals diagnosed with autism. Furthermore, these findings provide novel therapeutic targets within the gastrointestinal tract with potential benefits for people living with autism spectrum disorder.

A/Prof Elisa Hill-Yardin leads the Gut-brain Axis laboratory at RMIT University, Bundoora, Australia focused on i) identifying the cause of gut dysfunction in transgenic mouse models of neurological disease, ii) determining how neurons communicate with the lymphoid system and inflammation, and iii) understanding interactions between the nervous system and bacteria.

Prof Hill-Yardin received her PhD in Neuroscience from The University of Melbourne (2002) and subsequently moved to Paris, France to take up a CNRS postdoctoral role in the team of Prof Bertrand Lambolez to study cortical neuronal diversity using single cell RT-PCR in combination with patch clamp electrophysiology. She returned to Melbourne as an NHMRC Howard Florey Centenary Fellow in 2006 to join the laboratory of Prof Steve Petrou to investigate changes in neuronal networks in genetic mouse models of epilepsy.

Traditionally, when we think of behavior and neurological disorders, we think about the brain. Most of the current focus in neuroscience has been based on identifying key brain regions, specific genetic variants associated with neurological disorders, relevant molecular mechanisms, and selective circuits that give rise to overt behavioral and internal neuronal states.

Consequently, current therapeutic approaches for neurological disorders aim to target the brain directly.

However, we are the bearers not only our own genomes, but also the genomes of the microbes living with us. As we now appreciate, symbiotic microbes are fundamental to nearly every aspect of host function and fitness. Serendipitously, Costa-Mattioli and colleagues have recently discovered that microbes in the gut can modulate brain function and behaviors in an amazingly powerful way.

Here, Costa-Mattioli describes his efforts to elucidate one the biggest challenges in microbiome research, that is the identification of the mechanism(s) by which a given bacterial strain (or bacterial community) regulates a selective behavior or disease state.

He discusses the different approaches his laboratory is using to dissect the causation of how particular microbes (and their metabolic byproducts) impact brain development and function, as well as well as the signals, structures and mechanisms that regulate the gut-microbiome-interactions in both health and disease.

Dr. Costa-Mattioli is a Professor in the Department of Neuroscience, and director of the Memory and Brain Research Center (MBRC) at Baylor College of Medicine. He received his bachelor’s degree in microbiology from the Faculty of Science (Montevideo, Uruguay), his master’s degree and PhD from the Pierre and Marie Curie University and University of Nantes, respectively. He conducted his postdoctoral training at McGill University in Montreal Canada.

Costa-Mattioli is interested in understanding the mechanisms underlying complex behaviors. His lab encompasses two complementary lines of research. The first one, more traditional but very important, aims at unraveling the molecular mechanisms underlying memory formation and cognitive dysfunction. The second line of research, more recent and relatively unexplored, is focused on understanding how gut microbes control CNS driven-behavior and brain function.

His work has not only impacted the neurobiology of memory and cognitive disorders, but also industry efforts to develop drugs that enhance memory. Finally, Mauro has won numerous awards, including the International Eppendorf & Science Prize in Neurobiology, the Searle Scholar award, the International Society for Neurochemistry’s Young Investigator Award, and more recently the UCSF Presidential Chair award. He also serves in the editorial board of Neuron, Scientific Report and Frontiers in Neuroscience.

Brain development and behavioral responses are influenced by gut microbiota. Perturbations of the microbiota-gut-brain axis have been identified in autism spectrum disorders (ASD), suggesting that the microbiota could be involved in abnormal social and stereotyped behaviors in ASD patients.

Notably, changes in microbiota composition and fecal, serum or urine levels of microbial metabolites are associated with ASD. Yet, a causal relationship between abnormal microbiota composition, altered microbial metabolite production, and ASD remains to be demonstrated.

We hypothesized that p-Cresol (also known as 4-Cresol), a microbial metabolite that was described as more abundant in ASD patients, contributes to ASD core behavioral symptoms. Here we show that mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition.

Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Also, social behavior deficits were transferrable from p-Cresol-treated mice to control mice by fecal matter transplantation. In contrast, the microbiota from control mice restored both social interactions and dopamine neurons excitability when transplanted to p-Cresol-treated mice.

Altogether, these results suggest that microbial metabolites p-Cresol could be involved in the development of core autistic behaviors via a gut microbiota-dependent mechanism. Further, this study paves the way for therapeutic interventions targeting the production of p-Cresol by gut bacteria to treat patients with ASD.

Dr Laetitia Davidovic has been a CNRS researcher at the Institut de Pharmacologie Moléculaire et Cellulaire (Valbonne, France) since 2009. Her research interests encompass molecular and cellular bases of neurodevelopmental and psychiatric disorders through the exploration of murine models combining omics, physiological and behavioral explorations to systems biology approaches.

After 12 years working on Fragile X Syndrome, leading monogenic cause of intellectual disability and autism, Laetitia Davidovic joined Prof. Nicolas Glaichenhaus’ Team Immunity, brain and peripheral nerves in 2016 to study immune dysfunctions associated to neurodevelopmental disorders.

She has been developing a new line of research to understand the modulatory role of the gut microbiota and its associated metabolites on the brain and behavior, in the context of normal or pathological functioning of the brain, using environmental mouse models of psychiatric disorders. In parallel, she develops a translational approach based on the identification of biological signatures of diseases or behavioral traits in cohorts of autistic and schizophrenic patients as well as in mother-child cohorts sampled from the general population.

This presentation summarizes the status of genetic discovery in ASD, and give examples of how gene discovery can contribute to novel therapeutics.

There have been significant strides in identifying both rare and common genetic variants that are associated with ASD. More than 100 genes have been identified that, when mutated with rare deleterious variants, are associated with high risk for ASD and associated disorders.

These genes, and the associated mutations, can be studied in model systems to provide windows into the biology processes that lead to ASD. Such insights, in turn, can lead to novel therapeutic approaches for these rare genetic disorders. Genetics, therefore, provides one mechanism to stratify ASD subjects and to develop precision medicine approaches.

Joseph D. Buxbaum, PhD is a Professor of Psychiatry, Genetics and Genomic Sciences, and Neuroscience, and serves as the Director of the Seaver Autism Center for Research and Treatment and is Vice Chair for Research and for Mentoring in the Department of Psychiatry.

Dr. Buxbaum is a molecular neuroscientist whose research aims to understand the molecular and genetic basis of autism spectrum disorder and associated neurodevelopmental disorders, with the goal of developing novel therapeutics.

Dr. Buxbaum is a founder and communicating Principal Investigator of the Autism Sequencing Consortium, currently analyzing whole exome sequencing from 50,000 individuals to identify ASD genes. In addition, his lab has numerous human stem cell lines ongoing and has characterized more than a dozen rodent models for ASD and associated disorders.

Dr. Buxbaum received his BSc in Math and Biology from Touro College, and his MSc and PhD in Neurobiology from the Weizmann Institute of Science in Israel. Dr. Buxbaum completed a Postdoctoral Fellowship in Molecular and Cellular Neuroscience at the Rockefeller University and was elected to the National Academy of Medicine in 2015.

This presentation discusses evidence supporting the role of folate in fetal brain development and the consequences of folate insufficiency. It also discusses folate receptor autoimmune disorder and its effect on pregnancy and fetal development.

Edward Quadros, PhD is a Research Professor at SUNY – Downstate in the Departments of Medicine and Cell Biology. His research interests include biochemical and molecular aspects of vitamin B12 / folate absorption, transport and metabolism; Genetic abnormalities of vitamin B12 / folate dependent pathways; Cellular and metabolic consequences of vitamin B12 and folate deficiencies; Vitamin B12, folate and homocysteine metabolism in the elderly population with cardiovascular disease and cognitive disorders including Alzheimer’s dementia; Neuropathology of vitamin B12 and folate deficiency; B12, folate status and DNA methylation in the brain.

Another area of research actively being pursued in Dr. Quadros’ laboratory is the association of folate receptor autoimmunity with neural tube defect pregnancy and cerebral folate deficiency. Current research is focused on fetal and neonatal brain development and the role of folate and B12 in this process. Another aspect of Dr. Quadros’ research is focused on cancer therapeutics based on vitamin B12 and folate analogs that are anti-metabolites, drug-conjugates and pro-drugs; selective targeting of drugs via the B12 and folate transport proteins and their receptors; vitamin B12 and folate depletion strategies to inhibit cell replication in malignancies utilizing monoclonal antibodies to block cellular uptake of these vitamins and to deliver drugs.

IL-17a has been highly conserved during evolution of the immune system and recent studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, we characterized a population of γδ17 T cells in the meningeal spaces of healthy mice and described their contribution to the brain homeostasis. Physiological release of IL-17a by meningeal γδ17 T cells was correlated with anxiety-like behavior and was partially dependent on TCR engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons and its genetic deletion decreased anxiety-like behavior.

Given the growing interest in the neuroimmune interactions, these findings shed new light on the understanding of neuropsychiatric conditions and support further research on the development of new therapeutic targets.

Dr. Kalil Alves de Lima is a postdoctoral fellow in Jony Kipnis’ lab at Washington University School of Medicine in St. Louis, MO. Alves de Lima completed his graduate training in immunology at the University of Sao Paulo, studying the regulation of IL-17a in TH17 cells using experimental models of autoimmune diseases. Funded by the Sao Paulo Research Foundation (FAPESP), Alves de Lima joined the lab of Dr. Francisco Quintana at Harvard Medical School as a visiting scholar where he explored the effects of environmental factors on CNS-resident cells during the development of neuroinflammatory conditions.

Currently, Alves de Lima’s work focuses on understanding the neuroimmune connections between meningeal immunity, neural activity and motivated behavior in homeostasis and disease. His most recent publication highlights a unique population of IL-17a-producing meningeal γδ T cells which regulate anxiety-like behavior in mice.

Paul Ashwood, Ph.D., is a Professor in the Department of Medical Microbiology and Immunology and with the M.I.N.D. Institute at the University of California at Davis. He earned his Ph.D. at King’s College London where he focused on how environmental exposures cause inflammation in gastrointestinal diseases. He received further research training in stem cell biology at Cancer Research UK and post-doctoral research training on autism at University College London.

His current studies are at the forefront of a rapidly evolving field of investigation into the role that immune response plays in neurodevelopmental conditions such as autism. He was the first to demonstrate links between immune dysfunction and the severity of impairments that are hallmark features of autism such as social interactions and communication.

Overall, Dr. Ashwood has worked across traditional disciplinary boundaries to examine connections between different biological systems during development in order to understand how they lead to the characteristic features of autism.

Specifically, he has highlighted the importance of innate immune pathways, gut-immune-brain connections and the presence of autoimmunity in some children with autism. He is author of over 100 articles on autism and has received recognition for his innovative work.

Despite numerous years of research, individuals with autism has been left without an effective treatment that can alleviate their suffering. This might be due to the complexity of autism and an incomplete understanding of the biological underpinnings such as poor knowledge of interplay between genetic, molecular, and cellular and network biology, and impoverished models which fail to capture the complex biology. Moreover, disease mechanisms are mainly investigated after the clinically manifestation of symptoms. Thus the underlying biological process might have already taken place and not be detectable any longer.

Objectives: Therefore, we aim to “turn back time” and model the developing brain of the individual. For this, we are using patients derived human induced pluripotent stem cell based three dimensional brain organoids, so called mini-brains. In combining with a multi-time-point, multi-omic approach with followed a computational decision support tools to mimic the possible pathogenic events we are creating a platform for individualized diagnostics and treatment. We aim to create deep phenotypic profiles of both patients derived brain organoids as well as those from healthy individuals during the individual’s brain development. Hence creating precision diagnostics and precision treatment for the individual.

Individuals with autism suffer from multiple co-morbid conditions. Immune mediated inflammation that affects not only the brain but also other organs has been implicated in many of the observed clinical features of autism.

However, inflammation in autism appears not associated with specific environmental factors, but appears to be driven by innate immune memory (IIM) responses that are generated by metabolic and epigenetic changes triggered by an initial stimulus.

Dr Jyonouchi’s research attempts to determine the underlying mechanisms of immune mediated inflammation and their effects on the development and progress of Autism Spectrum Disorder ASD. The central hypothesis is that mal-adapted IIM results in dysregulated innate immune responses to multiple, unrelated environmental factors, leading to puzzling arrays of clinical features and multiple co-morbid conditions in ASD.

Dr Jyonouchi is a board certified allergist/immunologist practicing at Saint Peter’s University Hospital, and a Clinical Professor of Pediatrics at Rutgers Robert Wood Johnson Medical School. She is the recipient of a number of honors and awards, and has served on NIH grant review committees and Editorial Boards. She has had continuous grant support since 1989 and is the author of over 100 published peer-reviewed articles and chapters. Her research interests include: neuro-immune interactions and epigenetic regulation in children with ASD, innate immune abnormalities in patients with mucosal inflammation of the airway (asthma) and the GI tract, and non-IgE mediated food allergy.

Marion Leboyer, M.D., Ph.D. is Professor of Psychiatry at the University of Paris Est (UPEC) in Créteil, France. She is head of the University-affiliated department of Psychiatry (Hôpitaux Universitaires Mondor, Assistance-Publique-Hôpitaux de Paris). She also runs the laboratory “Translational Psychiatry” (http://www.imrb.inserm.fr/equipes/m-l…) which is part of Mondor Institute (Inserm U955).

Since 2007, she is the executive director of a non profit foundation, “Fondation FondaMental” (www.fondation-fondamental.org) created by the French Ministry of Research. Dr. Leboyer has authored or co-authored 480 peer-reviewed international publications (H-factor = 73) on autism spectrum disorder and major affective and psychotic disorder.

Her research efforts contributed to a better identification of genetic and environmental risk factors associated with major psychiatric disorders towards better understanding of causal mechanisms. In particular, she has contributed to the identification of mutations of genes implicated in synaptogenesis in autism, associations of genetic vulnerability factors in bipolar disorders, discovery of immune dysfunctions, environmental risk factors as well as brain imaging abnormalities.

Her goal is to develop diagnostic tools to better identify homogenous subgroups of psychiatric disorders paving the way to mechanisms-based treatments. Within the expert center networks centers created and coordinated by Fondation FondaMental, several cohorts of patients have been followed allowing for the construction of shared observational databases. These networks have enabled multiple collaborations within different national and international research programs.

Dr Leboyer is the principal investigator of several international and national research projects funded by the National Research Agency and by the French Ministry of Health.

Changes in inflammatory markers are seen in the blood and brains of some people with autism. While these markers are traditionally thought of as indicators of an altered immune response, research has revealed an unexpected, critical role for many immune proteins and cells in the healthy developing and adult brain.

This talk provides examples of these “moonlighting markers”, outline some of what we have learned about their roles in the healthy nervous system, and discuss how this information expands our interpretation of inflammatory changes when they accompany altered brain development and function.

Dr. Boulanger received her Ph.D. in Neuroscience from the University of California, San Diego working with Dr. Mu-ming Poo, and performed postdoctoral research at Harvard Medical School with Dr. Carla Shatz. While at Harvard, Dr. Boulanger was a Junior Fellow in the Harvard Society of Fellows. She accepted a faculty position in Neuroscience at the University of California, San Diego, where she was the Silvio Varon Professor of Neuroregeneration, and moved her lab to the Princeton University in 2009, where she is a tenured Associate Professor in the Princeton Neuroscience Institute. She is the recipient of numerous awards, including an Alfred P. Sloan Research Award, a Whitehall Foundation Award, the James Howard McGregor Prize, and an award from the Ray Thomas Edwards Foundation.

The goal of research in Dr. Boulanger’s laboratory is to understand how neuro-immune crosstalk contributes to the formation, function, modification, and disruption of neural circuits.

Randy D. Blakely, a native of Columbus, Georgia, is Professor of Biomedical Science in the Charles E. Schmidt College of Medicine at Florida Atlantic University and the founding Executive Director of the FAU Brain Institute.

Prior to his arrival at FAU in 2016, Blakely held the Allan D. Bass Chair in Pharmacology & Psychiatry at the Vanderbilt University School of Medicine for 21 years (1995-2016) and when appointed, was the youngest to hold an endowed chair in university history. At Vanderbilt, Blakely directed the Center for Molecular Neuroscience, the Vanderbilt/NIMH Silvio O. Conte Center for Neuroscience Research, and the Vanderbilt/NIMH Postdoctoral Training Program in Functional Neurogenomics.

In 1998, Blakely and Dr. Elaine Sanders-Bush launched the Vanderbilt Brain Institute and generated a nationally-prominent Ph.D. Program in Neuroscience.

Over the past 30 years, Blakely’s laboratory has investigated the genetics, structure, regulation and pathophysiology of these and other synaptic transporters, and was the first to identify clinical syndromes associated with heritable mutations in neurotransmitter transporter genes, linking these mutations to cardiovascular, behavioral, and neuromuscular disorders. Blakely’s research has appeared in more than 330 publications in high-impact journals including Science, Nature, The New England Journal of Medicine, Neuron and the Proceedings of the National Academy of Sciences, USA. He has served on multiple editorial boards including the Journal of Neuroscience, Journal of Biological Chemistry, and Molecular Pharmacology.

His expertise has also drawn appointments to multiple federal, foundation advisory scientific advisory boards including appointment as Chair of the Board of Scientific Counselors for the National Institute of Mental Health (NIMH), as well as his current position as a member of the NIMH National Advisory Mental Health Council where he advises the NIMH Director and program staff on national research and funding priorities.

➤ Cerebral Folate Deficiency syndromes and their major origin attributed to folate receptor-alpha autoantibodies.
➤The discovery of severe infantile Autism associated with neurological deficits in a number of patients with Cerebral Folate Deficiency.
➤ Subsequent studies on brain folate deficiency in Autism Spectrum Disorders.
➤The diagnosis, treatment and prevention in children and parents with Folate receptor autoantibodies as an important biomarker.

Vincent Ramaekers is Professor emeritus in Child Neurology and Director of the Center for Autism at the University Hospital, Liège, Belgium. He is also Professor at the Medical Faculty of Aachen University. His main scientific interests and contributions are novel neurometabolic syndromes, vitamin-responsive disorders and autism spectrum disorders. He contributed to the discovery of the clinical phenotype, aetiology and treatment of a new emerging group of disorders, now known as the “cerebral folate deficiency syndromes”. His research is conducted in close collaboration with Prof Edward Quadros and Jeffrey Sequeira at SUNY Downstate, New York and Prof Beat Thöny at Zurich University.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormal behavior and social interaction along with delayed speech and developmental milestones. Current knowledge points to abnormal brain development during fetal life and infancy contributing to the neurologic deficits. The genetic, metabolic and environmental factors contributing to ASD remain elusive.

While a combination of factors may underlie each clinical phenotype, recently, folate receptor autoimmune disorder has emerged as the single most common abnormality in the immediate family and the affected children.

Blocking and / or binding autoantibodies against the folate receptor alpha (FRα) have been identified in ~70% of children with ASD. These antibodies can block folate transport from the mother to the fetus and in infants, folate uptake into the brain; resulting in cerebral folate deficiency. In clinical trials folinic acid treatment has shown significant efficacy in improving the core symptoms of ASD

Evidence in support of the observations has come from a rat model of folate deficiency and exposure to rat folate receptor antibodies during gestation. Exposure to FRαab during gestation produces severe learning, memory and cognitive impairment in otherwise normal appearing offspring. Maternal antibody exposure produces local inflammation in the placenta and blocks folate delivery to the fetus. Co-administration folinic acid and dexamethasone can prevent the behavioral deficits in pups. In young rat pups, FRαab accumulates in the brain and blocks folate uptake.

Restoring cerebral folate can normalize multiple metabolic functions including neurotransmitters and gene expression. This has clear implications in the treatment and prevention of ASD associated with FRα autoantibodies.

Edward Quadros, PhD is a Research Professor at SUNY – Downstate in the Departments of Medicine and Cell Biology. His research interests include biochemical and molecular aspects of vitamin B12 / folate absorption, transport and metabolism; Genetic abnormalities of vitamin B12 / folate dependent pathways; Cellular and metabolic consequences of vitamin B12 and folate deficiencies; Vitamin B12, folate and homocysteine metabolism in the elderly population with cardiovascular disease and cognitive disorders including Alzheimer’s dementia; Neuropathology of vitamin B12 and folate deficiency; B12, folate status and DNA methylation in the brain.

Another area of research actively being pursued in Dr. Quadros’ laboratory is the association of folate receptor autoimmunity with neural tube defect pregnancy and cerebral folate deficiency. Current research is focused on fetal and neonatal brain development and the role of folate and B12 in this process. Another aspect of Dr. Quadros’ research is focused on cancer therapeutics based on vitamin B12 and folate analogs that are anti-metabolites, drug-conjugates and pro-drugs; selective targeting of drugs via the B12 and folate transport proteins and their receptors; vitamin B12 and folate depletion strategies to inhibit cell replication in malignancies utilizing monoclonal antibodies to block cellular uptake of these vitamins and to deliver drugs.

The explosion in knowledge, technology, and clinical capabilities regarding genetics and genetic testing has expanded greatly in this first part of the 21st Century. In the last half decade, these gains have rapidly been applied to individuals with autism. However, most families, and most clinicians, are unaware or confused in regards to which people should be tested, what tests to order, who can understand the vast and complicated information provided, how genetic and environmental factors interact, and what difference all this might make in terms of altering management and improving outcomes.

This talk addresses each of these issues. In addition, the emerging genetics of autism is discussed in order to understand how genetic testing can oftentimes help elucidate “candidate”, potentially-treatable, risk factors that predispose the individual patient to develop disease, as well as occasionally define an exact cause/diagnosis.

As costs have dropped substantially, the panel approach, which was state-of-the-art just a few years ago, has rapidly been replaced by sequencing all ~22,000 genes (whole exome sequencing), or literally sequencing the entire 3 billion base pairs of DNA (whole genome sequencing, WGS).

In this clinician’s experience, clinical improvement from a therapy suggested based on genetic data is present in more cases than it is absent, and improvement can occur in “core” autism areas (attention, behavior, anxiety, etc.) and/or in co-morbidities (nausea, fatigue, pain, etc.), as demonstrated in brief case reports.

Options for helping clinicians choose the appropriate test(s), and to understand how to use the reports in their practice, are discussed. Finally, cost reductions have allowed for most families to benefit from this technology, including frequent insurance coverage (if coded correctly), and some low-cost non-insurance options. Specific examples on how genetic testing can inform on clinical decision making are presented. Finally, how genetic testing has informed on what we see as “autism” really is will be discussed.

Richard Boles, MD is a Medical Geneticist with expertise in mitochondrial and other metabolic disorders. He completed medical school at UCLA, a pediatric residency at Harbor-UCLA, and a genetics fellowship at Yale. He received board certifications in Pediatrics, Clinical Genetics and Clinical Biochemical Genetics.

For over two decades, Dr. Boles’ clinical and research focus has been on sequence changes in genes involved in energy metabolism, and more recently ion channels, and their effects on the development of common functional disorders. Examples include autism, pain syndromes, cyclic vomiting, bowel dysmotility, dysautonomia, depression, and SIDS.

Dr. Boles practices the “bedside to bench to bedside” model of a physician-scientist, combining an active clinical practice with basic research into the underlying genetic predispositions leading to the same conditions. He has over 70 published papers and was a faculty member for 20 years at the Keck School of Medicine at USC and a practicing medical geneticist at Children’s Hospital Los Angeles.
Dr. Boles has been a pioneer in the new field of genomics in order to facilitate the translation of the vast amounts of acquired genetic knowledge into applications that improve routine medical care. He has consulted for four different genetics diagnostics companies for many years.

In addition, Dr. Boles currently is in private practice in Pasadena, California, and at the Rossignol Medical Center in Aliso Viejo, California. Dr. Boles has joined The Center for Neurological and Neurodevelopmental Health in New Jersey in order to provide telemedicine services to help physicians and families how to translate modern genetics testing into practice treatment options. He also does legal consulting. Although he generally tries to really listen to what his patients and families are saying, for at least 20 years many of them have been asking for a comprehensive nutritional product based on his clinical practices. He has (finally) done this with Spectrum Needs.

Individuals with autism suffer from multiple co-morbid conditions. Immune mediated inflammation that affects not only the brain but also other organs has been implicated in many of the observed clinical features of autism.

Richard Frye, MD, PhD is a Child Neurologist with expertise in neurodevelopmental and neurometabolic disorders. He received an MD and PhD in Physiology and Biophysics from Georgetown University and completed his Child Neurology Residency and Fellowship in Behavioral Neurology and Learning Disabilities at Harvard University/ Children’s Hospital Boston. He has authored over 150 peer-reviewed publications and book chapters, and serves on several editorial boards. He has conducted several clinical trials demonstrating the efficacy of safe and novel treatments that target underlying physiological abnormalities in children with ASD. He is the Chief of Neurodevelopmental Disorders at the Barrow Neurological Institute at Phoenix Children’s Hospital.

James B. Adams, PhD is the Director of the Autism/Asperger’s Research Program at Arizona State University. His research focuses on the medical causes of autism and how to treat and prevent it including the areas of nutrition (vitamins/minerals, essential fatty acids, carnitine, digestive enzymes, special diets), oxidative stress, gut problems, gut bacteria, toxic metals, and seizures.

He has published over 150 peer-reviewed scientific articles, including over 40 related to autism. He is also the President of the Autism Society of Greater Phoenix, the President of the Autism Nutrition Research Center, the co-leader of the Scientific Advisory Committee of the Autism Research Institute, and chair of the Scientific Advisory Board of the Neurological Health Foundation. He has an adult daughter with autism.

Dr. Rosa Krajmalnik-Brown is the director of the Biodesign Center for Health Through Microbiomes and a Professor at the School of Sustainable Engineering and The Built Environment, at Arizona State University. She has a Ph.D. in Environmental Engineering from Georgia Tech. She was awarded an NSF CAREER award, was selected Fulton Engineering Exemplar Faculty, and was recently awarded Arizona Researcher of the year by AZBio.

Dr Krajmalnik-Brown has received funding for her research from many federal agencies including NIH, DoE, DoD, and NSF. She is a pioneer in research on gut microbiome and autism. She is author of 4 patents and more than 100 peer-reviewed publications.

She specializes on molecular microbial ecology for bioremediation, the use of microbial systems for bioenergy production, and the human intestinal microbial ecology and its relationship to obesity, bariatric surgery, metabolism, and autism

Individuals with autism suffer from multiple co-morbid conditions. Immune mediated inflammation that affects not only the brain but also other organs has been implicated in many of the observed clinical features of autism.

Microbial dysbiosis is a common finding in children with autism spectrum disorder (ASD), particularly in children with chronic GI symptoms. Although there is abundant literature reporting alterations in the GI microbiome composition in children with ASD, the measurements are typically derived from stool samples serving as a proxy for the intestinal lumen, and decisions regarding therapy are made using this information. While the egested fecal microbiome is easily accessed, it is not an optimal proxy for the GI tract mucosal microbiome, or for the luminal fecal microbiome above the descending colon. Data from specific locations within the mucosa of the GI tract would likely provide new and important information.

Having knowledge of the microbiome diversity in an anatomic location-specific manner throughout the gut may provide more relevant diagnostic and therapeutic insight for the treatment of children with ASD and chronic GI symptoms.

Stephen Walker, PhD is a Professor of Regenerative Medicine at the Wake Forest Institute for Regenerative Medicine (WFIRM) in the Wake Forest School of Medicine, Winston- Salem, NC. He received his PhD in Genetics and Developmental Biology at West Virginia University and was a Post-Doctoral Fellow in the Molecular Genetics Program at Wake Forest Baptist Health prior to joining the Department of Pediatrics faculty in the Section on Medical Genetics.

Dr. Walker’s group is focused on the application of integrated multi-omics approaches, using patient biospecimens, to understand the molecular basis for chronic gastrointestinal symptoms in children with an autism spectrum disorder diagnosis, and to understand how chronic GI problems early in childhood may impact neurodevelopment. The objective of this work is to identify clinically relevant biological markers that can be used for diagnosis and/or as therapeutic targets to the benefit of this vulnerable and underserved population.

This talk described our initial efforts aimed at mapping the gastrointestinal microbiome in GI-symptomatic children with ASD.

The increased prevalence of gastrointestinal symptoms in patients with autism compared to healthy controls has been extensively proved, with a potential secondary impact on children’s behaviours. From a physiopathological point of view, dysbiosis associated to impaired gastrointestinal permeability have been suggested as possible triggers thus altering the normal nervous system functions.
Dietary or pharmacological interventions are often utilized, however, results are still debated.

In this uncertain context, the existence of a possible link between gastrointestinal inflammation and neuropsychiatric disorders need to be clarified in the way to find the right dietetic and pharmacological tools to obtain the best effects on bowel and neurological inflammatory process and for this reason improvement of gastrointestinal and autistic symptoms.

Our study confirmed the high prevalence of gastrointestinal symptoms and pathological microscopic histological alterations in 339 patients with autism that underwent upper and lower endoscopy with biopsies in our unit. A significant association between clinical manifestations and histological alterations has been identified with a significant improvement of clinical and neuropsychiatric symptoms after dietetic and pharmacological treatment of the intestinal inflammation.

Further controlled prospective studies are required in order to confirm these correlations and permit to treat this category of patients at the very early onset of gastrointestinal symptoms in the way to obtain better clinical results unfortunately nor reachable if later attempted for the natural achievement of the complete altered neurological development.

Arthur Krigsman, MD is a pediatrician and pediatric gastroenterologist with expertise in the evaluation and treatment of autism associated gastrointestinal problems. His interest in this unique patient population began in 2001 and during the ensuing 17 years he has treated over 1900 children from across the globe suffering from autism and a variety of gastrointestinal problems.

His research interest lies in the characterization of the unique cellular, molecular, and clinical features of ASD-associated inflammatory bowel disease and his original findings appear in numerous peer-reviewed journals.

In addition to serving as an invited reviewer for peer-reviewed medical journal author submissions in his area of expertise, Dr. Krigsman has served as a guest lecturer on the topic of gastrointestinal disease and autism at national and international scientific meetings, hospital Grand Rounds both here and abroad, Nurse Association meetings, philanthropic organizations, and at numerous lay medical conferences. He has also presented his findings before the U.S. Congress. His greatest satisfaction though derives from the clinical care he provides his patients and in the improved quality of life that results from diagnosing and treating gastrointestinal disease in this vulnerable population.

He maintains offices in both New York City and Austin, Texas.

As a specialist in gastroenterology, internal medicine and hepatology, Dr. Hazan has used her expertise in many regards over the last two decades. Dr. Hazan is the founder & CEO of Progenabiome, a genetic sequencing research laboratory whose interest is to understand the clinical implications of the microbiome. Progenabiome has 42+ ongoing clinical trials investigating the microbiome and disease and six COVID-19 studies validating testing, prophylaxis, and treatment protocols for the novel coronavirus. It was the first lab to find the whole genome of SARS-CoV-2 in 100% of infected patients’ stools.

Dr. Hazan is also the CEO of Ventura Clinical Trials, where she conducts and oversees clinical trials for cutting-edge research on various medical issues. She is a top clinical investigator for multiple pharmaceutical companies and has participated in over 300 clinical trials. She has also run a successful private practice, Malibu Specialty Center, for over 20 years.

Dr. Hazan acts as the series editor of Practical Gastroenterology on the microbiome, a peer review journal that reaches 18,000 gastroenterologists. She is a speaker for World Congress of Digestive Disease, MAGI, Microbiome Congress, International Drug Discovery Science and Technology Conference and NIST (National Institute of Standards and Technology).

Inducted as a member of the American Pediatric Society, a member of the Society for Pediatric Research, and an American Gastroenterology Association Fellow (AGAF), an honor bestowed by the AGA and AAP for superior professional achievement in the field of Pediatrics and Gastroenterology.

Dr. Michail is also a reviewer/chair reviewer for many institutions and societies including the National Institute of Health, the American Gastroenterological Association, North American Society of Pediatric Gastroenterology and Nutrition, the Southern California Clinical and Translational Science Institute, etc. She is also a reviewer for major medical journals and abstract reviewer for several medical societies and has served on the editorial board of journals. She is an invited lecturer at the national and international levels.

Dr. Michail has been named best doctor by LA magazine and Pasadena Magazine.

What existing drugs can be used as therapeutics for reducing the core symptoms of Autism Spectrum Disorder?

Dr Jyonouchi is a board certified allergist/immunologist practicing at Saint Peter’s University Hospital, and a Clinical Professor of Pediatrics at Rutgers Robert Wood Johnson Medical School. She is the recipient of a number of honors and awards, and has served on NIH grant review committees and Editorial Boards. She has had continuous grant support since 1989 and is the author of over 100 published peer-reviewed articles and chapters. Her research interests include: neuro-immune interactions and epigenetic regulation in children with ASD, innate immune abnormalities in patients with mucosal inflammation of the airway (asthma) and the GI tract, and non-IgE mediated food allergy.

Autism is associated with gastrointestinal symptoms that occur at a four-fold greater rate than in neurotypical individuals. The degree of social impairment in ASD is highly correlated with the severity of GI disorder. The adverse behavioral manifestations of ASD are accentuated during episodes of abnormal GI function.

Irritable bowel syndrome (IBS), frequently begins in childhood. Children with IBS have evidence of enteric serotonergic dysfunction. A strong relationship also exists between intestinal infection and IBS, supporting the idea that epigenetic alterations in developing enteric neurons causes lasting changes in the enteric nervous system (ENS).

These effects need not be prenatal because enteric neurons continue to be born postnatally and even in mature animals.

In addition to genetic abnormalities, psychosocial trauma, stress, drugs, infection, and inflammation alter serotonergic neuronal activity and thus also change availability of serotonin in the developing ENS. The aberrant concentration of active serotonin could provide a common pathway for events, from the psychological to the infectious/inflammatory, to influence the properties of the mature ENS.

This process may also provide insight into the genesis of GI dysfunction that accompanies ASD and perhaps additional CNS disorders.

Michael D. Gershon, Professor of Pathology and Cell Biology at Columbia University Medical Centre, has been called the “father of neurogastroenterology” because, in addition to his seminal work on neuronal control of gastrointestinal (GI) behavior and development of the enteric nervous system (ENS), his classic trade book, The Second Brain, has made physicians, scientists, and the lay public aware of the significance of the unique ability of the ENS to regulate GI activity in the absence of input from the brain and spinal cord.

Dr. Gershon has published almost 450 peer-reviewed papers. Major contributions, which have relevance to disorders of GI motility, including irritable bowel syndrome, include identification of serotonin as a GI neurotransmitter and the initial observation in the gut of intrinsic sensory nerve cells that trigger propulsive motor activity.

Dr. Gershon has called serotonin “a sword and shield of the bowel” because it is simultaneously proinflammatory and neuroprotective. Mucosal serotonin triggers inflammatory responses that oppose microbial invasion, while neuronal serotonin protects the ENS from the damage that inflammation would otherwise cause. Neuron-derived serotonin also mobilizes precursor cells, which are present in the adult gut, to initiate the genesis of new neurons, an adult function that reflects a similar essential activity of early-born serotonergic neurons in late fetal and early neonatal life to promote development of late-born sets of enteric neurons.

More recently, Drs. Michael and Anne Gershon have demonstrated that varicella zoster virus (VZV) infects, becomes latent, and reactivates in enteric neurons. They have demonstrated that “enteric zoster (shingles)” occurs and may thus be an unexpected cause of a variety of gastrointestinal disorders, the pathogenesis of which is currently unknown.

ENS is the largest and most complex unit of the peripheral nervous system and is the only component able to function without input from the brain or spinal cord. The complexity of the ENS provides ample opportunity for developmental abnormalities to occur. When they do occur they disturb the function of the bowel for long periods, often a lifetime.

Daniel Rossignol, MD, Phoenix Children’s Hospital; Harumi Jyonouchi, MD, Saint Peter’s Hospital; Arthur Krigsman, MD, Pediatric Gastro-Enterologist; James Adams, PhD, ASU; Ann Ming Yeh, MD, Stanford University.

This discussion panel was part of Synchrony 2020 Online Symposium – ‘From Bench to Biopharma’, organised by the The BRAIN Foundation in partnership with UC Davis MIND Institute and CalTech.

Antonia Hardan MD is a Professor of Psychiatry and Behavioral Sciences – Child and Adolescent Psychiatry at Stanford Hospital and ClinicsLucile Packard Children’s Hospital.

His research expertise is in the neurobiology of autism and in the development of innovative treatment. He served as a principal investigator on numerous projects examining the neurobiology of autism and assessing the effectiveness of a wide range of interventions. He is the recipient of an R01 (MH083972) “A Neuroimaging Study of Twin Pairs with Autism” and a pilot grant from Autism Speaks examining the effectiveness of pivotal response group treatment for parents of young children with autism. He has completed several investigations aimed toward increasing our understanding of the pathophysiology of pervasive developmental disorders while applying multimodal imaging techniques.

Dr. Hardan has also led several clinical trials examining the effectiveness of novel interventions such as N-acetylcysteine and pivotal response group training in children with autism.

Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology, pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation, and novel applications of cord blood in the emerging fields of cellular therapies and regenerative medicine.

Dr. Kurtzberg serves as the Director of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Blood and Marrow Transplant Program, Director of the Carolinas Cord Blood Bank, and Co-Director of the Stem Cell Transplant Laboratory at Duke University.

Dr. Kurtzberg’s research in MC3 focuses on translational studies from bench to bedside, seeking to develop transformative clinical therapies using cells, tissues, molecules, genes, and biomaterials to treat diseases and injuries that currently lack effective treatments.

Recent areas of investigation in MC3, which are funded by the Marcus Foundation, include the use of autologous cord blood in children with neonatal brain injury, cerebral palsy, and autism, as well as preclinical studies manufacturing microglial oligodendrocyte-like cells from cord blood to treat patients with acquired and genetic brain diseases. Studies of donor cord blood cells in adults with stroke and children with cerebral palsy and autism are also underway.

Dr. Kurtzberg’s lab has developed novel chemotherapeutic drugs for T-cell Leukemias, assays enumerating ALDH bright cells to predict cord blood potency from segments attached to cryopreserved cord blood units, and is performing translational research testing cord blood expansion, cellular targeted therapies and tissue repair and regeneration. Dr. Kurtzberg currently holds several INDs for investigational clinical trials.

In this talk Dr. Aran describes possible roles of the endocannabinoid system in the pathogenesis of Autism, and discusses the current evidence for cannabinoid treatment in ASD including a still unpublished randomized study. After the talk, there is a 5 minutes for questions and comments.

Dr. Aran’s research projects over the past years combine basic science with bedside clinical observations. Examples include: researching the genetic basis of familial microcephaly in a local cohort and uncovering the affected protein and its function (Aran et al, Neurology 2016) and similar projects on congenital pre-synaptic myasthenia gravis (Aran et al, Neurology 2017), progressive cerebellar atrophy (Langer & Aran et al, J Med Genet 2018) and intellectual disability with refractory seizures (Segel & Aran et al, Neurogenetics 2020).

In recent years, Dr. Aran has focused his efforts on understanding the role of the endocannabinoid system in ASD and assessing the therapeutic effects of cannabidiol-based medical cannabis.

Dr. Aran and his team have initiated the first studies exploring the effects of cannabidiol-rich cannabis in children with ASD, a subject that is getting now a lot of public attention worldwide. In the first study (Aran et al, JADD 2019) they demonstrated the feasibility of whole plant extracts of cannabidiol-rich strains, in 60 children with ASD and severe resistant behavioral problems. Following this study, they have conducted a double-blind, placebo-controlled trial in 150 children with ASD, to compare the efficacy of pure cannabinoids and a whole plant extract that preserve a possible entourage effect.

As part of this study they have measured baseline circulating endocannabinoids and found substantially lower levels in children with ASD compared with a matched control group. These findings corroborate in humans, previous studies in animal models that demonstrated dysregulation of the endocannabinoid system in ASD and suggest a therapeutic role for cannabidiol. (Aran et al, Mol. Autism 2019).

Arthur Krigsman, MD is a pediatrician and pediatric gastroenterologist with expertise in the evaluation and treatment of autism associated gastrointestinal problems. His interest in this unique patient population began in 2001 and during the ensuing 17 years he has treated over 1900 children from across the globe suffering from autism and a variety of gastrointestinal problems.

His research interest lies in the characterization of the unique cellular, molecular, and clinical features of ASD-associated inflammatory bowel disease and his original findings appear in numerous peer-reviewed journals.

In addition to serving as an invited reviewer for peer-reviewed medical journal author submissions in his area of expertise, Dr. Krigsman has served as a guest lecturer on the topic of gastrointestinal disease and autism at national and international scientific meetings, hospital Grand Rounds both here and abroad, Nurse Association meetings, philanthropic organizations, and at numerous lay medical conferences. He has also presented his findings before the U.S. Congress. His greatest satisfaction though derives from the clinical care he provides his patients and in the improved quality of life that results from diagnosing and treating gastrointestinal disease in this vulnerable population.

The developing brain is not a small adult brain. Neurons follow developmental sequences with a progressive modification of their electrical properties. Immature cells present ionic currents and patterns that are unique to them and help validating the formation of brain networks, enabling cells to fire and connect together. I have suggested that an insult, whether genetic or environmental, deviates developmental sequences leading to neurons that remain “immature” in the adult brain, presenting immature patterns and aberrant connections and leading to neurodevelopmental disorders.

Based on this concept, called the Neuroarcheology concept, I propose that these immature ensembles are the cause of the disorder. Now, it is widely accepted that Autism Spectrum Disorders (ASD) are “born” in utero and therefore, according to this hypothesis, neurons might keep immature features. We confirmed this in animal models relying on the universal development of intracellular concentrations of chloride ([Cl-]i) and GABA actions.

Indeed, we discovered 3 decades ago a developmental shift from neurons with high [Cl-]i and excitatory actions of GABA to low [Cl-]i and inhibitory GABA actions. We hypothesized that in ASD neurons have high [Cl-]i as if they have remained immature, and we’ve shown that this was the case in rodent models of drug-induced-ASD, Fragile-X and Rett syndromes, and Maternal Immune Activation.

Also, we demonstrated that restoring low [Cl-]i and GABAergic inhibition with an antagonist of the main chloride importer (Bumetanide) attenuates autism severity. Relying on these observations, we have performed two phase II clinical trials showing that Bumetanide attenuates the severity of autism in children and adolescents.

In parallel studies and to further evaluate the role of the Neuroarcheology concept in ASD, we have recently shown that neurons grow during parturition and birth in autistic rats but not in age-matched naïve ones, indicating a perturbation of the in utero developmental process by the pathogenic inaugurating event.

The identification of persistent immature features will enable to develop novel treatments using agents that selectively silence these neuronal ensembles, performing a sort of pharmaceutical surgery. This approach will not “cure” ASD but will significantly attenuate it.

ABOUT THE SPEAKER:
After a PhD dedicated to mechanisms of memory processes, and 2 postdoctoral fellowships dedicated to epilepsies, I was nominated head of a French Medical Research council Unit (INSERM) in Paris in the largest maternity hospital (1986).

Dedicating my work on recording immature neurons, my colleagues and I discovered fundamental features including the GABA/Chloride shift and early immature patterns. I then moved to Marseille to create and direct the Mediterranean Institute of Neurobiology (INMED) animating studies directed on how the brain prepares for birth.

My current basic research work performed in the Neurochlore company is centered on maternity and birth in relation to brain disorders and based on the Neuroarcheology concept. This concept calls for a new way of studying and treating developmental disorders hoping to attenuate its severity by blocking the immature features of neurons that have been impacted by the inaugurating in utero insult.

Arthur Krigsman, MD is a pediatrician and pediatric gastroenterologist with expertise in the evaluation and treatment of autism associated gastrointestinal problems. His interest in this unique patient population began in 2001 and during the ensuing 17 years he has treated over 1900 children from across the globe suffering from autism and a variety of gastrointestinal problems.

His research interest lies in the characterization of the unique cellular, molecular, and clinical features of ASD-associated inflammatory bowel disease and his original findings appear in numerous peer-reviewed journals.

In addition to serving as an invited reviewer for peer-reviewed medical journal author submissions in his area of expertise, Dr. Krigsman has served as a guest lecturer on the topic of gastrointestinal disease and autism at national and international scientific meetings, hospital Grand Rounds both here and abroad, Nurse Association meetings, philanthropic organizations, and at numerous lay medical conferences. He has also presented his findings before the U.S. Congress. His greatest satisfaction though derives from the clinical care he provides his patients and in the improved quality of life that results from diagnosing and treating gastrointestinal disease in this vulnerable population.

He maintains offices in both New York City and Austin, Texas.

Peter has a Master’s degree in Engineering from Imperial College, London and an MBA from INSEAD in Fontainebleau, France. Peter comes from a family of doctors, who were all taught that Autism is untreatable. Peter discovered after trialing Bumetanide in 2012 that his son’s autism does respond to drug therapy. He then developed a personalized polytherapy, the autism Polypill, to treat his son’s specific phenotype.

He shares the published research and his own insights via his blog Epiphany ASD, with parents, doctors and even some researchers: https://epiphanyasd.blogspot.com/

Peter is a member of the Scientific Advisory Board of the Pitt Hopkins Research Foundation.
Based on this concept, called the Neuroarcheology concept, I propose that these immature ensembles are the cause of the disorder. Now, it is widely accepted that Autism Spectrum Disorders (ASD) are “born” in utero and therefore, according to this hypothesis, neurons might keep immature features. We confirmed this in animal models relying on the universal development of intracellular concentrations of chloride ([Cl-]i) and GABA actions.

Indeed, we discovered 3 decades ago a developmental shift from neurons with high [Cl-]i and excitatory actions of GABA to low [Cl-]i and inhibitory GABA actions. We hypothesized that in ASD neurons have high [Cl-]i as if they have remained immature, and we’ve shown that this was the case in rodent models of drug-induced-ASD, Fragile-X and Rett syndromes, and Maternal Immune Activation.

Also, we demonstrated that restoring low [Cl-]i and GABAergic inhibition with an antagonist of the main chloride importer (Bumetanide) attenuates autism severity. Relying on these observations, we have performed two phase II clinical trials showing that Bumetanide attenuates the severity of autism in children and adolescents.

In parallel studies and to further evaluate the role of the Neuroarcheology concept in ASD, we have recently shown that neurons grow during parturition and birth in autistic rats but not in age-matched naïve ones, indicating a perturbation of the in utero developmental process by the pathogenic inaugurating event.

The identification of persistent immature features will enable to develop novel treatments using agents that selectively silence these neuronal ensembles, performing a sort of pharmaceutical surgery. This approach will not “cure” ASD but will significantly attenuate it.

ABOUT THE SPEAKER:
After a PhD dedicated to mechanisms of memory processes, and 2 postdoctoral fellowships dedicated to epilepsies, I was nominated head of a French Medical Research council Unit (INSERM) in Paris in the largest maternity hospital (1986).

Dedicating my work on recording immature neurons, my colleagues and I discovered fundamental features including the GABA/Chloride shift and early immature patterns. I then moved to Marseille to create and direct the Mediterranean Institute of Neurobiology (INMED) animating studies directed on how the brain prepares for birth.

My current basic research work performed in the Neurochlore company is centered on maternity and birth in relation to brain disorders and based on the Neuroarcheology concept. This concept calls for a new way of studying and treating developmental disorders hoping to attenuate its severity by blocking the immature features of neurons that have been impacted by the inaugurating in utero insult.

An overview and demonstration of various photobiomodulation devices used for treating neurological conditions, including autism spectrum disorder.

Photobiomodulation describes the use of visible red and infrared light energy to stimulate, heal, regenerate, and protect cells that have experienced injury or degeneration or at risk of dying. There is a 50-year history of demonstrated effectiveness in treating wounds and a variety of musculoskeletal conditions.

Over the past decade, research and clinical evidence are now illuminating the positive benefits of applying photobiomodulation to the head to treat neurological disorders.

Michael R Hamblin Ph.D. was a Principal Investigator at the Wellman Center for Photomedicine at Massachusetts General Hospital, an Associate Professor of Dermatology at Harvard Medical School and is now a Distinguished Visiting Professor at the University of Johannesburg, South Africa. He gained his PhD in organic chemistry from Trent University in England.

His research interests include photodynamic therapy, photobiomodulation drug delivery, nanomedicine, and tissue engineering. His research program was supported by NIH, CDMRP, USAFOSR and CIMIT. He has published over 560 peer-reviewed articles, over 150 conference proceedings, book chapters and International abstracts and holds 10 patents. He is Editor-in Chief of “Photobiomodulation, Photomedicine and Laser Surgery”, Associate Editor for 10 journals, on the editorial board of a further 20 journals.

He has an h-factor 113 and 52,000 citations. He has authored/edited 25 textbooks on PDT and photomedicine including 13 SPIE proceedings. Dr Hamblin was elected as a Fellow of SPIE in 2011, received the 1st Endre Mester Lifetime Achievement Award from NAALT in 2017, the Outstanding Career Award from the Dose Response Society, and the 1st Ali Javan award for Photobiomodulation Basic Science Research from WALT in 2018.

Margaret Naeser, PhD, is located at the Boston VA Medical Center, and is Research Professor of Neurology, Boston University School of Medicine. Since 2009, she has studied the effect of red/near-infrared (NIR) light-emitting diodes (LED) placed over the scalp/brain to treat sequelae of traumatic brain injury (TBI), PTSD, stroke/Aphasia, Dementia, Gulf War Illness, and most recently, retired, Pro-Football players possibly developing chronic traumatic encephalopathy (CTE).

She has a strong interest in neuroplasticity and utilizing transcranial photobiomodulation (tPBM) to promote neuromodulation for brain recovery. This includes studying changes in functional connectivity on fMRI scans within specific, intrinsic neural networks which are damaged (but not destroyed), in various central nervous system disorders.

She has had VA-/ NIH-funded research for over 40 years, with early emphasis on neuroanatomy of stroke location in the brain, on CT/MRI scans in patients who have language problems (Aphasia). She has published research using transcranial magnetic brain stimulation in (rTMS) to improve language in chronic stroke/Aphasia. She has over 100 publications.

She is on the editorial board, Photobiomodulation, Photomedicine and Laser Surgery (PMLS) and Fellow, American Society for Lasers in Medicine and Surgery (ASLMS). Full disclosure, some of her transcranial LED research with TBI is funded by Vielight, Inc. (Toronto, Canada), and Thor Photomedicine (London, UK).

Transcranial Photobiomodulation Therapy is a safe and feasible treatment approach that has the potential to treat core features of ASD. Further research is necessary and warranted.

Dr. Cassano is an Assistant Professor in Psychiatry at Harvard Medical School, and Director of Photobiomodulation at the Massachusetts General Hospital (MGH) Division of Neuropsychiatry and at the MGH Depression Clinical and Research Program.

He graduated from the MGH-McLean Adult Psychiatry Residency Program in June 2009. Since 2009, he has served as PI on multiple studies on Transcranial Photobiomodulation (tPBM) for several neuropsychiatric disorders –such as major depressive disorder (MDD) and generalized anxiety disorder (GAD)– sponsored by the Brain and Behavior Research Foundation (NARSAD), by the Dupont Warren/Livingston Fellowship from Harvard Medical School and by private companies. These groundbreaking projects ─in collaboration with the MGH Wellman Center for Photomedicine─ have led to very promising results; they have demonstrated preliminary efficacy of near-infrared radiation for the treatment of mood disorders and for ameliorating cognition. Considerable press attention stemmed from these studies, with CNN and Washington Post coverage at the national level.

At the MGH Neuropsychiatry and Neuromodulation lab, he is actively pursuing the identification of biological targets of the effects of tPBM: he has been the PI on a pilot study to investigate the effects of tPBM on cerebral blood flow (Diffuse Correlation Spectroscopy – DCS), on brain electrical activity (electroencephalography – EEG), autonomic reactivity (heart rate variability – HRV and skin conductance – SCR) and cognition in healthy subjects.

Dr. Cassano is particularly interested in studying tPBM, as a pro-cognitive intervention, in patients with cognitive impairment and has reported with other groups on the use of tPBM to treat chronic traumatic brain injury and Down Syndrome, as well as to enhance cognition in healthy volunteers.
Dr. Cassano’s research on tPBM is currently funded by the National Institute of Mental Health (NIMH), by the National Institute of Aging (NIA), by the Alzheimer Association “Part the Cloud” and by the Down Syndrome Research Foundation (UK).

Kanwaljit Singh, MD, MPH is the Executive Director of C-Path’s International Neonatal Consortium (INC) and Director of Pediatric Programs in Tucson, Arizona. Dr. Singh comes to C-Path from University of Massachusetts Medical School (UMass), Worcester, MA, where he worked for more than seven years as Instructor of Pediatric Neurology.

At UMass, Dr. Singh’s research focused on evaluating novel treatment options for Autism Spectrum Disorders (ASD) and evaluating the safety and efficacy of a small molecule (Sulforaphane) present in broccoli sprouts in the treatment of ASD.

Dr. Singh has also done extensive research and has numerous publications in pediatric epilepsy. Before UMass, he worked in ASD research at Lurie Center for Autism at Massachusetts General Hospital/Harvard Medical School in Boston. In addition to his research work, Dr. Singh also served on the IRB committees at Harvard Medical School and interacted with regulatory authorities, including the FDA.

Dr. So Hyun “Sophy” Kim is a clinical researcher with an extensive background in identification of early behavioral phenotypes and examining developmental trajectories of children with ASD. She has developed a new language assessment tool, the Observation of Spontaneous Expressive Language (OSEL), which is now undergoing a national norm based on a partnership with the publisher, WPS, in collaboration with Dr. Catherine Lord. She has also led the development of the new treatment outcome measure for ASD, the Brief Observation of Social Communication Change (BOSCC) with Dr. Catherine Lord.

Currently, she is a PI of a NIMH funded project designed to examine the mechanisms of early, parent-mediated interventions for toddlers with ASD (1R01MH114925-01). Most recently, Dr. Kim has led efforts to examine school readiness in kindergarteners with ASD while integrating behavioral and electrophysiological(ERP/EEG) methods, with a particular focus on executive function.

Restricted and repetitive behaviors (RRBs) constitute a core symptom domain in ASD and span a broad range of behaviors including repetitive sensory motor behaviors (RSMB), ritualized and rigid behaviors, compulsions, and restricted interests, regrouped as insistence on sameness (IS) behaviors. There is a high need for accurate and reliable assessments of RRBs in clinical trials. Yet, limited insight into the psychometric properties of existing RRB measures present a major obstacle to better understand underlying mechanisms and develop effective treatments.

In this talk Julian Tillman PhD describes findings from ongoing projects to refine measurement of RRBs in ASD and develop reliable clinical endpoints.

Currently, she is a PI of a NIMH funded project designed to examine the mechanisms of early, parent-mediated interventions for toddlers with ASD (1R01MH114925-01). Most recently, Dr. Kim has led efforts to examine school readiness in kindergarteners with ASD while integrating behavioral and electrophysiological(ERP/EEG) methods, with a particular focus on executive function.

Dr. Lisa Nowinski, Clinical Director of non-physician services at the Lurie Center for Autism and Instructor of Psychiatry at Harvard Medical School, is a clinical neuropsychologist with more than a decade of experience diagnosing and caring for individuals with autism spectrum disorder (ASD) and other neurodevelopmental disorders.

As Director of Clinical Psychology at the Lurie Center, Dr. Nowinski is responsible for all clinical psychology services and training. In addition to directing a robust assessment and therapy program, Dr. Nowinski runs a competitive postdoctoral fellowship – offering specialized training to clinical psychologists who seek to build expertise in the assessment and care of individuals with ASD.

Dr. Nowinski specializes in the diagnostic and neuropsychological assessment of individuals with autism spectrum disorder across the lifespan. She is involved in a number of medication and therapeutic intervention clinical trials, where she is responsible for consultation on study design, data collection, comprehensive subject phenotyping, and outcome measures. Dr. Nowinski is also a member of the Autism Treatment Network’s Behavioral Scientist Committee where she has worked with professionals from around the country to improve care for patients and families with ASD.

Dr. Campbell is the Senior Vice President of R&D at Axial Therapeutics. He brings 25 years of drug discovery and development experience to Axial. He has built and led R&D teams in early-stage research through to advanced clinical development in small start-ups to mid-sized companies. Prior to joining Axial, Dr. Campbell held various leadership roles at companies including CordenPharma, Surface Logix, Insmed and Boehringer-Ingelheim. Dr. Campbell served as VP of R&D at Ancora Pharmaceuticals, successfully triaging the company through the acquisition by Corden Pharma. While at Surface Logix and Insmed, Dr. Campbell played an integral role in the discovery and development of five clinical drug candidates, including TAK-609 (Phase 3, Takeda) and belumosudil (NDA stage, Kadmon). Prior to post-doctoral research at Duke, Dr. Campbell obtained a PhD in Chemistry from Queen’s University (Canada). He has consulted for several start-up companies in multiple capacities and is co-inventor on more than 15 issued patents.

Discussion on the development of therapeutics in the ASD space. Learning from our recent phase 2 and 3 clinical trials and how we are moving forward.

Veronique Crutel holds a Doctor of Pharmacy degree from the Free University of Brussels, Belgium and an advanced studies degree in Radiopharmaceuticals from the French National Institute for Nuclear Science and Technology. She received a PhD in CNS PET-Scan Radiopharmaceuticals from Paris XI University in 1996. She transitioned then to the pharmaceutical industry and after a few years working for a contract research organization, she joined Servier in 2000 as a project leader in the cardiology department. In 2004, she moved to the neuropsychiatric department, working on the development of compounds in depression and schizophrenia.

Since 2016, she has been leading as a project director a multidisciplinary team on the development of Bumetanide in Autism Spectrum Disorder (ASD).

This talk reviews the clinical development in ASD of bumetanide, as well as the regulatory requirements for the clinical development of medicinal products for the treatment of ASD.

Dr Padina is a licensed clinical psychologist and work as a clinician and compound development team leader in Neuroscience at Janssen. He leads several teams focused on developing novel treatments for mood disorders, Autism Spectrum Disorder (ASD), including innovative programs to identify potential biomarkers for psychiatric and neurologic conditions.

He has worked extensively in Schizophrenia and in the neurocognitive symptoms of psychiatric and neurological disorders. He teaches as an adjunct associate professor at a medical school in NJ, in psychiatry residency program and the psychology internship.

With Joan Fallon CEO, Curemark; Gahan Pandina, PhD, Jannsen R&D US (JNJ); Stewart Campbell, PhD Senior VP, R&D, Axial Therapeutics
Kevin Sanders, MD, Franchise Head Neurodevelopment- Product Development, Roche/Genentech; Rosa Krajmalnik-Brown, PhD, Professor and Center Director, Arizona State University; James Adams, PhD, President’s Professor, ASU; Véronique Crutel, PharmD, PhD, Project Director, Neuropsychiatry Center for Therapeutic Innovation, Servier, France.

What do you find when you look for 1000 environmental chemicals in children with Autism Spectrum Disorder? Do children with autism react differently than children without ASD to the same environmental chemicals? How can this be measured? How does the rising tide of manmade chemicals in our food chain, water, and air change the chemistry of children with and without ASD? What happens when stressed cells leak ATP?

In this talk Synchrony 2020 titled ‘Autism Metabolomics, Exposomics, and the Purinergic Stress Response’, Dr. Naviaux reports on his latest data that aims to answer these questions.

Robert Naviaux MD, PhD is a Professor of Genetics, in the Departments of Medicine, Pediatrics, and Pathology. He directs a core laboratory for metabolomics at UCSD. He is the co-founder and a former president of the Mitochondrial Medicine Society (MMS), and a founding associate editor of the journal Mitochondrion.

Dr Naviaux is an internationally known expert in human genetics, inborn errors of metabolism, metabolomics, and mitochondrial medicine. He is the discoverer of the cause of Alpers syndrome—the oldest Mendelian form of mitochondrial disease – and the developer of the first DNA test to diagnose it.

Dr.Naviaux’s lab has developed a number of advanced technologies like biocavity laser spectroscopy and mtDNA mutation detection by mass spectrometry. He is a Salk-trained virologist, and molecular and cell biologist, the inventor of the popular pCL retroviral gene transfer vectors, and was trained at NIH in tumor immunology and natural killer cell biology. He studied biochemistry at Georg-August University in Göttingen, Germany. He has been the PI for over 20 IRB-approved human subjects protocols at UCSD since 1995.

In 2010, Dr. Naviaux was a member of the Cal-Echoes oceanographic expedition to collect environmental and ecosystem data along the California coast. His work in ecosystem dynamics has guided new work in microbiome ecology and metabolism in autism spectrum disorders.

In 2011, he received a Trailblazer Award from Autism Speaks.

He is currently the director of the first FDA-approved clinical trial to study the safety and test the effects of suramin on behavior and language in children with autism.

This talk – ZYN002 Transdermal Cannabidiol Gel – Efficacy and Safety: Recent Clinical Research Advances in the Experimental Treatment of Autism (BRIGHT) and the Role of Methylation Status as a Prognostic Biomarker and Correlate to Disease Severity in Fragile X Syndrome – was part of first day of Synchrony 2020 Online Symposium – ‘From Bench to Biopharma’, organised by the The BRAIN Foundation in partnership with UC Davis MIND Institute and CalTech.

This talk, full title: ‘Novel Therapeutics Correct Excitatory/Inhibitory (E/I) Imbalance, Protect Synapses, and Improve Neurobehavioral Aspects of ASD’ – was part of first day of Synchrony 2020 Online Symposium – ‘From Bench to Biopharma’, organised by the The BRAIN Foundation in partnership with UC Davis MIND Institute and CalTech.

Investigation of CRS3123, a Narrow-spectrum Antibiotic, for the Treatment of Autism

Investigation of CRS3123, a Narrow-spectrum Antibiotic, for the Treatment of Autism

Creating an Integrated Framework to Enable Precision Medicine Drug Development and Clinical Trails in Autism Spectrum Disorder

As we gain increasing clarity on the biological architectures of autism, these conditions will rapidly become amenable to new therapeutic modalities (ranging from RNA-splicing small molecules to genomic medicine techniques, and beyond).

This talk describes the striking reach of these new therapeutic modalities to highlight a key challenge: to actually develop these medicines, we need scalable approaches not only for target identification, but also for prospective identification of those most likely to respond using biomarkers relevant to their pharmacodynamic effects.

After introducing the nature of this “joint identification” problem, Chris Chatham then describes the key features of potential solutions to this challenge and reports on our progress along these lines in partnership with academia, autism advocacy groups, and other industrial partners.

Dr Alessio Fasano is a world-renowned pediatric gastroenterologist, research scientist and entrepreneur. He is chief of Pediatric Gastroenterology and Nutrition at MassGeneral Hospital for Children (MGHfC).

Dr. Fasano directs the Center for Celiac Research, specializing in the treatment of patients of all ages with gluten-related disorders, including celiac disease, wheat allergy and gluten sensitivity. He treats patients with acute and chronic diarrheal diseases, and treats infants and children who have difficult-to-treat gastrointestinal problems.

He also directs the Mucosal Immunology and Biology Research Center and is associate chief for Basic, Clinical and Translational Research. Under his leadership, investigators are studying the molecular mechanisms of autoimmune disorders including celiac disease, and other-gluten-related disorders.

Dr. Fasano has been named visiting professor of pediatrics at Harvard Medical School. He authored the groundbreaking study in 2003 that established the rate of celiac disease at one in 133 Americans.

Widely sought after by national and international media, Dr. Fasano has been featured in hundreds of interviews including outlets such as The New York Times, The Wall Street Journal; National Public Radio; CNN; Bloomberg News, and others.

The most recent data, animal models supporting the pathologic significance of maternal autoantibody related (MAR) autoantibodies in autism. This talk outlines the discovery and development of MAR-related autism, and the clinical manifestations and symptoms of MAR.

Judy Van de Water, PhD, is a Professor of Medicine at the University of California, Davis. She is the Deputy Director of the UC Davis MIND Institute, and Co-Director of the NICHD-funded MIND Institute Intellectual and Developmental Disabilities Research Center. Dr. Van de Water’s research program has a strong focus on the immunobiological aspects associated with autism and other neurodevelopmental disorders including the maternal gestational immune environment, and how perturbation during gestation can impact the developing brain. Her work encompasses both the cellular response and humoral immune response during pregnancy and how this relates to neurobehavioral disorders such as autism and schizophrenia.

Autism is estimated to affect 1 in 59 children in the US and yet, except for rare genetic causes, the etiology in most ASD cases remains unknown.

The presence of increased inflammatory proteins and transcripts in a majority of ASD brain indicates there is an ongoing innate immune response in a large proportion of ASD cases.

We evaluate for adaptive immune cells and damage typical of immune cell mediated cytotoxicity that could potentially drive an innate immune response in the ASD postmortem brain. We found elevated number of lymphocytes in perivascular cuffs that correlates to the quantity of astrocyte-derived round membranous blebs forming from the glia limitans into the perivascular CSF spaces.

Bleb formation is a known cytotoxic reaction to targeted lymphocyte attack and astrocyte blebs are a histologic feature so far unique to ASD. Consistent with an immune cell-mediated injury at perivascular CSF-brain barriers, a subset of white matter vessels had an expanded perivascular space (with jagged contours) and increased perivascular collagen in ASD compared to control brains. Similar T-lymphocyte and astrocyte bleb pathology is observed in subarachnoid and pial surfaces of the cerebral cortex in ASD.

The findings suggest dysregulated cellular immunity may target damage of astrocytes at foci along the glia limitans CSF-brain barrier in many cases of ASD.

Matthew P. Anderson, M.D., Ph.D., is Director of Neuropathology, Beth Israel Deaconess Medical Center; Neuropathologist of Autism BrainNet; and Faculty, Harvard Medical School Ph.D. Program. He won the International Distinguished Dissertation Award (top Ph.D. thesis in science in U.S.A. and Canada, awarded once every 5 years) for seminal work with HHMI Investigator Michael Welsh by uncovering the ion channel and regulatory functions of the cystic fibrosis gene product (Cell, Science, Nature, and PNAS).

At Harvard, his laboratory leverages groundbreaking technologies to investigate the circuit and molecular basis of genetic forms of human neurological and psychiatric disease including epilepsy and autism. His laboratory identified the first human genetic epilepsy disorder with defective postnatal developmental pruning and maturation of glutamatergic circuits (Zhou et al. Nature Medicine 2009). They created the first genetic mouse model of a frequent and strongly penetrant genetic autism spectrum disorder (maternal 15q11-13 triplications; Smith et al. Science TM 2011).

The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) evaluated the viability of a battery of EEG and eye-tracking (ET) assays of social communication in ASD for use in clinical trials. The study enrolled 280 rigorously characterized children with ASD (6-11 years; IQ 60-150) and 119 typically developing (TD) control subjects. Two biomarkers, the EEG-based N170 to Upright Human Faces and the ET-based Oculomotor Index of Gaze to Human Faces have been accepted into the FDA’s Center for Drug Evaluation and Research Biomarker Qualification Program.

This lecture reviews ABC-CT study design and results of the first study and provides an overview of the planned second phase of the study.

The importance of biomarkers for ASD screening, diagnosis, and treatment – expert panel discussion with:

🔸Alessio Fasano, MD (Speaker) Division Chief, W. Allan Walker Chair in Pediatric Gastroenterology and Nutrition, Harvard, Mass General Hospital

🔸 Matthew P. Anderson MD, PhD (Speaker) Associate Professor of Pathology (Neuropathology), Harvard Medical School/ Beth Israel Deaconess Medical Center

🔸John Slattery (Speaker) Chief Executive Officer, BioROSA Technologies

🔸Chris Chatham, PhD (Speaker) Senior Principal Scientist and Biomarker Experimental Medicine Lead, Roche Innovation Center, New York

🔸 Judy Van de Water (Speaker) University of California Davis

🔸 Moderated by: Richard Frye, MD, PhD (Session Chair) Child Neurologist, Phoenix Childrens’ Hospital

Autism Spectrum Disorders (ASD) are a group of neurological disorders that present with limited social communication/interaction and restricted, repetitive behaviors/interests. Because of this lack of biological knowledge, autism diagnoses are restricted to observational behavioral and psychometric tools. Confirmation and expansion of the unique metabolic abnormalities in children with autism that accurately distinguishes them from typically-developing children would not only strengthen diagnostic accuracy, but also provide insights into underlying pathophysiology and a personalized approach to treatment options.

This talk discussed how a combinations of metabolites could serve as potential biomarkers for ASD.