The BRAIN Foundation

Synchrony Symposia Highlights

Synchrony is the first and only international symposium on translational research in autism that brings together leading researchers, clinicians, industry leaders, investors and venture partners from the world over and more importantly, families touched by autism and other neurodevelopmental disorders, with the single minded mission to improve health and quality of life of people living with these disorders.

Synchrony 2022

Synchrony 2022 was an in-person event, held this year Dec 2-4 at the ZOHO conference center in Pleasanton, CA. Researchers, physicians and other decision makers shared their latest research and ideas.

RESEARCH ROUNDTABLES aimed to provide clarity and insight into treatment, innovation and product development. Consensus articles will be published by the Working Group during 2023.

RESEARCH TALKS spanned a wide range of subjects, from the role of gut microbiome to exploring transcranial photobiomodulation as a  treatment option in autism.

INDUSTRY TALKS featured commercial companies that are in the process of developing novel therapies and treatments with a potential for FDA approval for core or comorbid symptoms of autism. Several key players brought to the table foreseeable treatment options at various stages of FDA clinical trials and approval.

CME CREDITS: We are excited to announce that for the first time physicians and clinicians can now receive CME credits when they attend the Synchrony Symposium. The BRAIN Foundation, in partnership with CME Consultants, was able to provide these credits for continuing medical education, disseminating much needed information about current research in the field and provide a framework for improvement around the standard practices of care for individuals with autism along with the host of comorbid conditions, and other neurodevelopmental disorders, promoting optimal health and well being of the patients.

Synchrony 2022 Roundtables

WORKING GROUP TO CREATE CONSENSUS ARTICLE

SESSION CHAIR: JENNIFER FRANKOVICH, MD, MS Clinical Professor, Dept of Pediatrics, Stanford Children’s Health, Lucile Packard Children’s Hospital Stanford

PANEL: Elizabeth D. Mellins, MD, Stanford University, Harumi Jyonouchi, PhD, St. Peter’s University Hospital, Stephen J. Walker, PhD, Wake Forest Institute for Regenerative Medicine

This roundtable focussed on the important issue affecting adolescents and adults with autism who experience a sudden and dramatic exacerbations of symptoms including one or more of: seizures, sleep deprivation, loss of weight, pain, sudden worsening of behavior and impulse control, separation anxiety, mood changes etc. In some cases there is a sudden worsening of co-morbidities such as IBD. Patients have responded to some pharmaceutics. Participants discussed their clinical experiences and observations and possible next steps. The group decided on the framework of a consensus article to characterize the symptoms, diagnostics and possible standard of care for individuals with autism who present a sudden neuropsychiatric exacerbation or chronic relapsing-remitting symptoms in adolescence or adulthood.

SESSION CHAIR: GABRIEL BELFORT, MD, PHD, Vice President, Clinical Development Sciences, Axial Therapeutics Inc.

PANEL: Gabriel Belfort MD, PhD, Axial Therapeutics, Kevin Sanders MD, Roche/Genentech, Gahan Pandina PhD, Janssen Research and Development, Robert H. Ring PhD, Kaerus Bioscience Ltd., John Slattery, BioROSA Technologies, Joanna Sambor, MS, VP and Head of Regulatory at MapLight Therapeutics

This roundtable focussed on the FDA approval process and the challenges involved in getting a drug to the market that addressed comorbid or core autism symptoms. The possibility of having an FDA consortium to discuss and come to a consensus, while involving the key industry players involved in developing the drugs, in the decision making process was explored.

One of the next steps would be to put together an endpoint working group to create a registry for clinical endpoints.

SESSION CHAIR: JOHN SLATTERY, Co-founder, President & CEO, BioROSA

PANEL: Manish Arora, BDS, MPH, PhD, Icahn School of Medicine at Mount Sinai, Karen J. Parker, PhD, Stanford University, Robert H. Ring, PhD, Kaerus Bioscience Ltd., Kevin Sanders, MD, Roche/Genentech, Micheal Paul, PhD, MaraBio Systems Inc.

This session was well attended by clinicians, physicians, researchers from both academia and industry and parents. We heard from parents and their everyday struggles and there was a strong request for biomarkers for diagnosis representative of symptom severity in patients and that can predict clinical symptoms or events that in turn can help clinicians take a particular therapeutic approach.

The panel will work to provide guidelines and best practices for preclinical models, steps to replicate models in independent labs for independent verification and feasibility, and finally a strategy to get that model further validated/accepted to bridge translational gaps. The panel will document the challenges and hurdles in the process, and using regressive autism as an example, design a possible clinical trial for biomarker, budget and plan.

SESSION CHAIR: RICHARD FRYE, MD, PHD, Phoenix Children’s Hospital and University of Arizona College of Medicine-Phoenix

PANEL: Samuel Pleasure, MD, PhD, UCSF, James Adams, PhD, Arizona State University, Manuel Casanova, MD, University of South Carolina, John Gaitanis, MD, Brown University, Jeffrey Lewine, CEO/CSO, Center for Advanced Diagnostics, Evaluation and Therapeutics

This session addressed a critical problem of late-onset seizures in some of the individuals around adolescence or adulthood. The group included parents who spoke about their children who had this condition. The problem of lack of standard of care for seizures in this population was discussed. The possibility of late onset epilepsy is higher in this group than the typical population. A possible change to standard of care to allow for a more proactive diagnosis and treatment of seizures in this group was discussed. This working group will continue to discuss and publish a consensus statement on late onset seizures and changes in treatment protocols to improve outcomes and hopefully prevent epileptic disorders in more adult patients.

There is no other conference which covers such a wide variety, and with great depth, of research and clinical data concerning all aspects of the autism community.

Thomas Geraci, D.O., Board Certified Emergency Medicine Physician

Synchrony 2022 Research Talks

RANDY BLAKELY, PHD, Executive Director, Stiles-Nicholson Brain Institute and Florida Atlantic University College of Medicine: Does a Disrupted, Bidirectional Relationship Between Serotonin and Inflammatory Signaling Support ASD traits? Lessons from Model System Studies
Serotonin (5-HT) signaling in brain, gut and immune system modulate mechanisms involved in normal behavior, gastrointestinal function and innate/adaptive responses to stress and foreign pathogens, respectively. The high-affinity, SSRI sensitive serotonin (5-HT) transporter is the major mode of synaptic 5-HT inactivation and also supports normal GI development and function as well as platelet 5-HT accumulation. Stimulated by efforts to identify contributors to linkage of ASD traits, we identified five rare coding variants in SERT in subjects contributing to linkage at the genomic area where SERT (SLC6A4) is located. These variants all displayed SERT hyperfunction and a conspicuous insensitivity to SERT protein regulatory molecules, including p38a MAPK, a signaling enzyme well known to support inflammatory cytokine signaling, among other stressors. Additionally, we showed that the major inflammatory cytokine, IL-1b, stimulates SERT activity via p38a MAPK signaling. Mutant mice expressing the most common of the hyper-functional SERT coding substitutions noted above, Gly56Ala, were subsequently found to display tonic p38a MAPK SERT phosphorylation, increased 5-HT clearance rates in vivo, and multiple ASD-like biochemical (e.g. hyperserotonemia) and behavioral traits involving alterations in social communication and repetitive behavior. As 5-HT is known to suppress inflammatory signaling in the CNS, we hypothesized that SERT Ala56, with their increased ability to eliminate 5-HT following release, might in turn drive tonic inflammatory signaling. Indeed, our work shows evidence of a tonic elevation of inflammatory cytokines in multiple brain regions, including IL-1b, with a consistent observation of elevations in the midbrain site of 5-HT neurons. This finding is significant as 5-HT neurons express, in a sex and subregion-dependent manner, significant levels of IL-1 b receptors (IL-1R1). Finally, our new work demonstrates that IL-1b application to acute dorsal raphe brain slices leads to inhibition of tonic firing of 5-HT neurons, paralleling findings of reduced excitability of these cells in slices from SERT Ala56 mice. We propose that SERT Ala56 mice elaborate a state of tonic 5-HT dependent innate immune activation that leads to tonic suppression of 5-HT neuron activation, supporting deficits in ASD behaviors. Notably, SERT Ala56 mice also display hyperserotonemia and altered gut function, suggesting that altered 5-HT homeostasis, via its interactions with innate immune signaling, may contribute to ASD traits in humans, particularly those who exhibit hyperserotonemia.

NAVEEN NAGARAJAN, PHD, University of Utah: ‘Microglia specific circuit defects in repetitive form of ASD behaviors’

Our work identifies a novel neural circuit that controls repetitive Autistic-type grooming behavior in Hoxb8 mouse model. Hoxb8 gene is exclusively expressed in 30% of brain microglia. Notably, the loss of function of Hoxb8 gene that leads to repetitive grooming behavior, chronic anxiety and social behavioral dysfunction results in cortico-striatal circuit (CSC) defects. A deeper analysis within the cortico-striatal and hippocampal circuits led to surprise findings where Hoxb8 microglia within specific sub regions of the cortico-striatal and hippocampal circuit not only induces neuroinflammation in repetitive behavior-driven Autism-like neurobehavioral disease states but are also optogenetically active and generates site specific behavior upon microglia activation in a healthy brain. Recent experiments have revealed that Hoxb8 microglia utilizes calcium signaling as a mechanistic way to communicate with neurons within the CSC. The studies provide insights into how proper function of microglia is essential to maintain a healthy neural circuit required for the optimal behavioral function and how genetic defects in microglia could alter neural circuit function and drive Autism-specific behavioral output.

STEPHEN E.P. SMITH, PHD, University of Washington: ‘Identification of novel drug targets through the analysis of protein interaction network dysfunction

A large class of “synaptic” ASD-linked genes are expressed at excitatory glutamatergic synapses and play important roles in translating neuronal activity into biochemical signal transduction cascades. Our group uses quantitative multiplexed co-immunoprecipitation to monitor 400+ binary protein-protein interactions, allowing us to identify dynamic protein-protein interaction networks (PINs) that mediate signal transduction in WT mouse neurons, and to observe how ASD-linked mutations alter PIN network states. Previously, we demonstrated that a glutamate synapse PIN responds to NMDA receptor vs. metabotropic receptor stimulation by activating distinct modules of interactions in response to each type of stimulation. Here, we report that in FMR1 KO mice modeling Fragile X syndrome, the unstimulated PIN network state overlaps with WT+mGLUR stimulation, and that, following mGLUR stimulation of FMR1 neurons, no further network changes occur. The abnormal network state is driven by interactions involving FYN kinase, a network hub involved in 8/14 disrupted interactions. To attempt to correct this abnormal PIN state, we used Saracatinib (SCB), an FDA-phase 2 inhibitor of SRC-family kinases (which include FYN). Using an in vitro protein synthesis assay, we found that SCB normalized hyperactive protein synthesis in FMR1 mice, without altering levels in WT animals. We then treated FMR1 mice with SCB by oral gavage for one week, and found that abnormal 3-chamber social behavior and object recognition memory at 48hours were rescued, while repetitive grooming was not affected. These data suggest that SRC-family kinase inhibition may be a therapeutic option for FMR1 mice. More broadly, this work demonstrates our PIN-based strategy of identifying and normalizing molecular signal transduction deficits in mouse models of ASD.

BRITTANY NEEDHAM, PHD, Stark Neurosciences Research Institute, IUSM: ‘Gut microbial metabolites influence the brain and behavior in a preclinical and clinical ASD context

The gut microbiome harbors an immense pool of enzymes capable of modifying a wide array of chemical structural groups. Influence of this dense, dynamic metabolic activity and bidirectional flux of molecules between microbe and host extends beyond the gut into the entire body, including the brain. In fact, integration of molecular inputs from within the gut can shape animal health and behavior, with recent examples showing that an altered gut microbiota is sufficient to affect neurological symptoms in various models. However, mechanisms mediating gut-brain interactions remain poorly defined. By characterizing the byproducts of gut microbes, we observed that 4-ethylphenyl sulfate (4EPS) levels were elevated in ASD mouse models and in plasma samples from ASD children compared to controls. We engineered gut microbes to selectively produce 4EPS, and observed that it entered the brain and altered region-specific brain activity and functional connectivity. Further study unveiled 4EPS-dependent differences in oligodendrocyte development and anxiety-like behavior, and targeted pharmacologic treatments rescued these effects. Separate treatment with a gastrointestinal-restricted adsorbent reduced the circulating 4EPS levels and led to improvements in anxiety in preclinical and clinical contexts. This molecule-focused study opens the door to uncover routes of action that gut microbes have on overall health.

MAUDE DAVID, PHD, Oregon State University: ‘Multi-omics, microbiome, and behavioral studies show the importance of fatty acids metabolism in Autism Spectrum Disorder

Autism is a complex developmental condition which co-occurs with gastrointestinal symptoms. But mechanistic links between gut microbiome, their microbially produced metabolites, and ASD remains unclear. Here we report longitudinal multi-omics profiling of stool samples from the largest cohort of ASD subjects and their typically developing siblings from 116 families, including 16S rRNA amplicon sequencing, metagenomics, metatranscriptomics and metabolomics. We discovered that a mono-unsaturated fatty acid was significantly decreased in the stool samples of ASD subjects compared to their typically developing siblings. Feeding this fatty acid to CNTNAP2 mice, which mimics the core ASD symptoms, we observed significant changes in mouse brain gene expression related to neural development and significant phenotypic improvements in 3 behavioral assays measuring sociability, habituation and exploratory behaviors. Furthermore, lipidomics analysis revealed that CNTNAP2 mice model shows lower abundance of this specific mono-unsaturated fatty acid when compared to control C57BL/6J, mimicking observations from the human study. Supplementing the mono-unsaturated fatty acid restored its levels in plasma and shifted the lipidomic profiles of the liver of the ASD mice model towards the C57BL/6J controls. Altogether our results suggest that fatty acid metabolism and mitochondrial dysfunction are a key component of autism which can be modulated by diet supplementation.

RICHARD BOLES, MD, NeurAbilities Healthcare: ‘High Sensitivity for Monogenic Causal Diagnoses in Autism, Including De Novo Variants Representing Novel Disorders, with Trio Whole Genome Sequencing and Data Reanalysis’

High Sensitivity for Monogenic Causal Diagnoses in Autism, Including De Novo Variants Representing Novel Disorders, with Trio Whole Genome Sequencing and Data Reanalysis
The last decade has seen dramatic improvements in the proportion of the genome clinically sequenced (< 1% to > 99%) and bioinformatic tools. Rapidly shifting methodologies have complicated sensitivity measurements. To determine the current sensitivity, we analyzed the raw DNA sequencing files on the Variantyx bioinformatics platform for the last 20 autism patients with trio whole genome sequencing (WGS).
Monogenic causal diagnoses (MCD) were provided in 15/20 (75%) cases, including 11 with heterozygous de novo variants. 4/5 patients with seizures received MCDs. Only 7/15 of MCD cases had the variant listed on the laboratory report. The “missed” cases included genes with few (THOC2, SLC41A2) and no prior reports (TRPM2, PGAM5, MTMR4, GRIK1, CD177). Only de novo variants in genes previously associated with autism were labelled as MCD. 3/4 cases without an MCD had inherited variants likely related to disease. Overall, 16/20 (80%) of cases had treatment recommendation(s) based on DNA.
Our results demonstrate high yield of trio WGS for revealing molecular diagnoses in autism that is greatly enhanced by re-analyzing DNA sequencing files. Many are de novo and represent un/under-published conditions that are not within the scope of reporting by clinical laboratories. Genes resulting in autism and epilepsy substantially overlap.

BENJAMIN MARLOW, MBIOCHEM, ABPI, MBBS MRCPCH, PGCME, Cognition Health: ‘Building on research success in Alzheimer’s to make an impact in the field of Autism

Motivated to better understand and progress the treatment of neurological disorders across the whole lifespan, Re:Cognition Health (RCH) has been leading in the UK on over 70  global trials into Alzheimer’s; medicinal products and  identification of biomarkers (imaging and blood markers).

Set up in 2011, its multidisciplinary team of neuroradiologists, neurologists and psychologists are also at the forefront of Chronic Traumatic Encephalopathy (CTE) research and management.

RCH screens >10,000 patients per month for CNS clinical trials and is a top global recruiter for multiple international clinical trials.

RCH is now established in over 8 Centers in the UK and expanding currently, in the USA – Fairfax (Washington DC area), opening a Center in Houston in December 2022 and another in Chicago in Spring 2024.

Recent trials on our portfolio include;

  • Biogen Aducanumab (07 Jun 21): https://investors.biogen.com/news-releases/news-release-details/letter-biogens-ceo-aduhelm
  • Eli Lilly Donanemab (24 Jun 22): https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-receives-us-fdas-breakthrough-therapy
  • Alzheon Valiltramiprosate (19 Sep 22): 12-month readout
  • Eisai/Biogen Lecanemab (28 Sep 22): https://www.bbc.co.uk/news/health-63060019
  • TauRx Therepeutics Hydromethylthionine mesylate (HMTM) (06 Oct 22):

Autism

RCH is eager to have a similar impact on Autism research,  as it has delivered  with Alzheimer’s and neurodegeneration. The expert team recognises the similar biological mechanisms for certain ASD phenotypes (related to immune dysfunction) and is passionate to facilitate and drive research into biomarker identification and novel therapeutics. RCH is also developing with its academic partners, sophisticated  neuroimaging (DTI and MEG)  biomarkers for Chronic Traumatic Encephalopathy(CTE).

RCH wishes to  establish clinical partnerships with academic centres and pharma  to offer a bespoke and effective  clinical trials service,  alongside an expanding clinic pursuing excellence in investigation and management of Autism and related disorders.

The mix of industry, academic researchers, physicians, and families is a major strength in driving towards new treatments for autism.
James Adams PhD, Arizona State University

Synchrony 2022 Industry Talks

LYNN DURHAM, CEO, and BALTAZAR GOMEZ-MANCILLA, CMO, Stalicla: ‘Translating Precision Medicine for Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) are a group of prevalent and highly heterogeneous conditions characterized by impairment in “personal, social, academic, or occupational functioning” with onset early in development. NDDs include Autism Spectrum Disorder (ASD), Intellectual Disability (ID), Attention Deficit Hyperactivity Disorder (ADHD), communication disorders, specific learning disorders, and motor disorders; moreover, the definition can also include some neuropsychiatric disorders such as schizophrenia and bipolar disorder, and other neurological disorders such as cerebral palsy or epilepsy.

The recent advances in genotyping and sequencing technologies have propelled the identification of risk/causal genes, which have pointed to remarkable genetic heterogeneity among and within specific NDDs, including ASD. According to the current diagnostic criteria based on Diagnostic and Statistical Manual of Mental Disorders (5th Edition, i.e., DSM-5) (Baird, 2013), an individual with ASD must show deficits in social interaction and communication combined with at least two of four subdomains of restricted or repetitive behaviors. However, ASD remains characterized by high heterogeneity in its behavioral manifestations and very complex genetic underpinnings, furthermore and despite significant progress in genomic, the molecular neuropathology in ASD overlaps with
different neuropsychiatric disorders. All in one these data suggest the existence of subtypes of ASD (Masi et al., 2020). Therefore, efforts to categorize ASD and NDDS, must rely on defining a relationship between clinical symptoms and biological mechanisms to enable the emergence of biologically driven drug development and improve the outcome of clinical trials in the space. Along these lines, Database Endophenotyping Patient Identification (DEPI) technology (https://stalicla.com) was developed to enable the matching biologically defined populations of
patients with neurodevelopmental disorders (NDDs) with tailored treatments, with a first application to ASD. DEPI uses systems biology and artificial intelligence to identify clinical and molecular characteristics underlying specific subgroups of patients. Application of DEPI led to the identification and clinical validation of two biologically defined subgroups of patients with ASD, ASD Phenotype 1 and ASD-Phenotype 2 (ASD-Phen1, ASD-Phen2).

ASD-Phen1 is characterized by the presence of specific clinical signs and symptoms (CSSs) mirroring the effects of an over-activation of NRF2 and its related pathways and cAMP dysregulation. STP1, a PDE 4/3 inhibitor combined with NKCC1 inhibitor, was then identified by DEPI as a tailored treatment for ASD-Phen1. During the presentation, clinical & biological evidence supporting the construct validity of ASD- Phen1 will be summarized and STP1 clinical Phase1b results will be presented.

KATYA SVERDLOV, CEO, and EUGENIA STEINGOLD, CSO, Jelikalite: ‘Treating Autism with tPBM, New EEG Evidence

TPBM is emerging as a promising treatment modality for Autism Spectrum Disorder. JelikaLite is conducting an open label study with 20 participants, aged 2-7 years old. Each child receives tPBM, which is administered via the Cognilum device, developed by Jelikalite. Cognilum previously received from the FDA a of Breakthrough Device Designation. The device is stimulating targeted brain areas with pulsed near infra-red light. The treatment is administered over the course of 10 weeks, twice a week, for 6-12 minutes, following a short titration period. Each child received at least 16 sessions of full dosage of Cognilum treatment.  In addition, we collected EEG data from each child over the course of the study.

The current  results reveal: 1. Significant reduction of symptoms, as measured by the change in before and after Childhood Autism Rating Scores. 2. Significant decrease in the Delta Waves over the course of treatment. 3. Significant increase in the intensity of  Gamma Waves over the course of the treatment.

The results indicate that tPBM (possibly due to its anti-inflammatory effect) could be an effective treatment modality for ASD. Future research is needed to specify the possible underlying neuroinflammatory process as well as optimal  doses to personalize the treatment.

MANISH ARORA, BDS, MPH, PHD, CEO, Linus Biotechnology Inc.: ‘A Precision Exposome Biomarker Platform for Early Detection and Drug Development in ASD’

LinusBio is a patient-centric, precision exposome medicine company headquartered in New York, NY.  Originating from the world’s leading exposome laboratory at Mount Sinai Health System, Linus has developed a technology platform that builds on breakthroughs in exposome sequencing that provide a molecular map over time to study the non-genomic components of health and disease.

LinusBio’s program pipeline comprises precision exposome medicine biomarkers and target discovery across disease domains for which historically no molecular endpoints have been available in medical practice or for clinical trials, including autism spectrum disorder.

 LinusBio received US FDA Breakthrough Designation and European Union CE Mark for its autism biomarker that can be applied as early as birth. The LinusBio platform is also being used in Phase 2 autism drug trials, and separately in a Phase 2 trial of a microbiome product with Novozymes.

ROBERT MILLS, Director of Science, Precidiag Inc.: ‘Meta-analysis of the autism gut microbiome identifies factors influencing study discrepancies and machine learning classification’

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder and accumulating evidence has suggested that dysbiosis of the gut microbiome plays an essential role. However, a body of research has investigated the ASD gut microbiome without consensus as to whether or how the ASD microbiome differs from neurotypical children. We have recently evaluated the underlying factors leading to study discrepancies by performing a meta-analysis on reprocessed 16S ribosomal RNA gene amplicon (16S) sequencing data. We have also utilized machine learning (ML) and obtained increased accuracy in ASD classification. Our work provides compelling evidence that the gut microbiome is altered in ASD patients, and highlights novel factors that are important considerations for future studies focusing on biomarker discoveries, diagnostics and treatment of the disease.
PAUL SONG, MD, Vice Chairman and Senior Advisor at NKGen Biotch: ‘The Regulatory Role of Natural Killer Cells in Neuroinflammation and its Potential Therapeutic Role in ASD’

While neuroinflammation can be a potentially beneficial defense mechanism that initially protects the brain by inhibiting diverse pathogens and clearing cellular debris, persistent inflammation can adversely affect neuronal plasticity, impair memory, and is generally considered as a main driver of tissue damage in neurodegenerative disorders.

Whether the upregulation of CXC chemokine receptor expression on CD4+ T cells, presence of blood-brain barrier disruption, changes in white and grey matter, or abnormal synaptic growth and/or synapses density, all mechanisms indicate a possible role of neuroinflammation in the development of Autism Spectrum Disorder (ASD).

Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and viral infections by limiting their spread and subsequent tissue damage. They also play an important role in identifying and eliminating autoreactive CD4+ cells and damaged neurons.

Several studies have demonstrated an overall immune dysregulation in kids with ASD and increased prevalence of dysfunctional NK cells with low cytotoxicity.

We discuss the significance of NK cell dysfunction in neurodegenerative disease and present our preliminary clinical data with our enhanced activated autologous NK cell therapy in adult patients with advanced neurodegenerative diseases and explore it potential use in kids with ASD.

RICHARD FRYE, MD, PHD, Scientific Advisor, Aprofol: ‘Levoleucovorin Treatment for Autism Spectrum Disorder’

Autism Spectrum Disorder (ASD) affects about 1 in 44 children in the USA with effective treatments lacking. ASD is associated with several disruptions in folate metabolism, including a unique disruption in the transport of folate into the brain due to folate receptor alpha autoantibodies (FRAAs). Initially Phase II controlled clinical trials have shown that D,L- leucovorin, a reduced form of folate, can circumvent this blockage in folate transport and improve ASD symptoms, especially in those individuals positive for FRAAs. Additional Phase II multicenter clinical trials with the L-isomer of leucovorin, levoleucovorin manufactured by AprofolAG (Steinegg, Switzerland), in both preschool and school aged children with ASD are ongoing to confirm initial findings and identify additional biomarkers to predict response to treatment. This talk will discuss the previous and ongoing studies showing the effectiveness of leucovorin in children with ASD and other neurodevelopmental disorders such as Cerebral Folate Deficiency as well as discuss known and novel biomarkers under development.
An outstanding meeting with a clear purpose and focus, providing quality presentations from the basic science, clinical, and entrepreneurial perspectives.
Steve Walker PhD, Wake Forest School of Medicine

Synchrony 2022 Invited Speakers

MANISH ARORA, BDS, MPH, PHD, Icahn School of Medicine at Mount Sinai: ‘Harnessing the exposome to diagnose autism

coming soon

RICHARD FRYE, MD, PHD, Phoenix Children’s Hospital and University of Arizona College of Medicine-Phoenix: ‘Update on Mitochondrial Research

coming soon

T. ATILLA CERANOGLU, Director, Psychiatry Service, Shriners Hospital for Children Massachusetts Gen. Hospital, Boston, MA: ”Evaluation of Transcranial Photobiomodulation in Autism spectrum disorder: Double-blind, placebo-controlled, randomized clinical study of a novel approach

coming soon

JOHN GAITANIS, MD, Pediatric Neurologist, Epileptologist, Hasbro Children’s Hospital: ‘Medical Cannabis and Autism

coming soon

ALESSIO FASANO, MD, Division Chief, Pediatric Gastroenterology and Nutrition, Director, Center for Celiac Research and Treatment, Director, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children: ‘Evaluation of Zonulin Pathway for personalized treatment of Autism spectrum disorder using a humanized mouse model and human intestinal tissue
Many children with autism spectrum disorder (ASD) are characterized by gastrointestinal (GI) dysfunction yet it remains unknown whether GI comorbidities contribute to core behavioral symptoms. Clinical studies have reported increased intestinal permeability and elevated serum zonulin in patients. Zonulin is a protein identified as pre-haptoglobin-2 protein (pre-HP2; the precursor of HP2) that regulates barrier permeability and is stimulated by gut dysbiosis. Our aim is to determine if a predisposition for increased gut permeability (i.e., an HP2-2 genotype) synergizes with gut microbiota from ASD patients to exacerbate barrier permeability, inflammatory processes, and core behavioral deficits. We are using human intestinal organoids, zonulin-transgenic mice (Ztm), and the zonulin inhibitor AT1001 to generate pre-clinical data for targeted ASD treatments. We have new pilot data illustrating: 1) an over-representation of the HP2 allele compared to HP1 allele in ASD GI patients; 2) an increase in baseline intestinal permeability in HP2-2 intestinal monolayers derived from ASD organoids as compared to HP1-1 monolayers; 3) increased permeability of HP2-2 monolayers incubated with ASD stool supernatant as compared to HP1-1 monolayers and; 4) significant behavioral differences in Ztm HP2-2 mice that received human ASD fecal microbial transplant (FMT) as compared to wild-type HP1-1 mice that received control FMT.

ARTHUR KRIGSMAN, MD, Pediatric Gastroenterologist, Private Practice, New York, and STEPHEN WALKER, PHD, Professor, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine: ‘Improvement in Gastrointestinal Symptoms, Cognition and Behavior Upon Treatment of ASD- associated Enterocolitis’

coming soon

JOSEPH D. BUXBAUM, PHD, Professor of Psychiatry, Neuroscience, Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai: ‘From rare mutations to common treatments in ASD’

The latest exome-wide association study in neurodevelopmental disorders identified over 350 genes that harbor mutations strongly contributing to the risk for autism spectrum disorder (ASD) and developmental delay. To translate these findings into eventual therapeutics, we first need to investigate the functions of each of these genes and their mutations in the context of brain development. Studying each of these genes separately in animal or cell models is a daunting task.

By coupling CRISPR-Cas9 transcriptional repression (CRISPRi) to single-cell RNA sequencing (scRNA-seq), we have enabled the high-throughput perturbation of multiple ASD risk genes at once with a parallel functional readout of the transcriptional consequences. Using this technology, we have extracted functional signatures for 77 of the top ASD risk genes in human neural progenitor cells and neurons derived from induced pluripotent stem cells (iPSCs).

We have identified several ASD risk genes that altered cell fate specification when repressed. Several ASD risk genes pushed neural progenitor cells to adopt glial fates. Furthermore, we identified multiple ASD risk genes that altered neural differentiation, including some that accelerated or delayed this process. Finally, we found that ASD risk genes clustered by shared co-expression modules, indicating shared signatures.

JAMES ADAMS, PHD, Arizona State University: ‘Microbiota Transplant for Pitt Hopkins’

Pitt Hopkins Syndrome is a rare single-gene disorder that generally results in severe symptoms of intellectual disability, motor coordination impairments, autism, and chronic constipation. Microbiota transplant therapy (MTT) involving vancomycin, bowel cleanse, and 12 weeks of microbiota capsules was used to treat 6 children with PTHS. The study design was Part 1: randomized, double-blind, placebo-controlled; Part 2: placebo group switched to real treatment; Part 3: long-term evaluation.
In part 1, group A (treatment) generally improved more than group B (placebo) on medication usage, GI symptoms, pain, average of 29 PTHS symptoms, and clinical global impressions of GI and PTHS symptoms.
In part 2 and 3, group A generally retained their improvements and sometimes improved more, at 3 and 6 months after treatment stopped.
In part 2, group B generally had additional improvements, and those improvements generally remained at end of part 3 (3 months after treatment stopped).

HARUMI JYONOUCHI, MD, Allergy and Immunology, Saint Peter’s University Hospital: ‘Biomarkers of Innate Immune Memory in Autism Spectrum Disorders’

COVID-19 induces prolonged immune activation, affecting multiple organs referred as long COVID syndrome. Neuropsychiatric and neurological symptoms are common long COVID symptoms occurring even in individuals who suffered from mild acute symptoms. ASD children with a component of neuroinflammation, will be at a higher risk of suffering from long COVID-19. Since the surge of omicron variants, we have treated numbers of ASD and non-ASD subjects who have been suffering from post-COVID neuropsychiatric symptoms. It is also our experience that long COVID symptoms are under-appreciated and under-treated in ASD children whose behavioral changes are attributed to “just being autistic” or changes associated with puberty. We present representative cases of long-COVID syndrome with predominant neuropsychiatric symptoms in ASD and non-ASD subjects. Since SARS-CoV-2 is a ssRNA virus that activates type 1 IFNs and down-stream signaling pathways, it is expected that immune-parameters that are affected by type 1 IFNs signaling pathways will be altered in patients with long COVID; clinical features of long COVID also overlap with clinical presentation in subjects suffering from genetic conditions caused by excessive type 1 IFN production (interferonopathies). We have preliminary data supporting this assumption and such results will be presented as well.

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