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 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
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.
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.
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.
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.
Synchrony 2022 Research Talks
NAVEEN NAGARAJAN, PHD, University of Utah: ‘Microglia specific circuit defects in repetitive form of ASD behaviors’
STEPHEN E.P. SMITH, PHD, University of Washington: ‘Identification of novel drug targets through the analysis of protein interaction network dysfunction‘
BRITTANY NEEDHAM, PHD, Stark Neurosciences Research Institute, IUSM: ‘Gut microbial metabolites influence the brain and behavior in a preclinical and clinical ASD context‘
MAUDE DAVID, PHD, Oregon State University: ‘Multi-omics, microbiome, and behavioral studies show the importance of fatty acids metabolism in Autism Spectrum Disorder‘
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’
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):
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.
Synchrony 2022 Industry Talks
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.
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’
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’
Synchrony 2022 Invited Speakers
MANISH ARORA, BDS, MPH, PHD, Icahn School of Medicine at Mount Sinai: ‘Harnessing the exposome to diagnose autism‘
RICHARD FRYE, MD, PHD, Phoenix Children’s Hospital and University of Arizona College of Medicine-Phoenix: ‘Update on Mitochondrial Research‘
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‘
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’
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’
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’