The BRAIN Foundation

Synchrony Symposium 2021 Highlights

Synchrony 2021 was a live online event, held on the December 11-12. Researchers, physicians and other decision makers shared their latest research and ideas.

RESEARCH TALKS spanned a wide range of subjects, from mitochondrial research in ASD to gene-microbiome interactions and the role of zonlin in gut permeability in a mouse model of 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.

Synchrony 2021 Research Talks

Richard E Frye MD, PhD, Neurologist, Phoenix Children’s Hospital and University of Arizona College of Medicine-Phoenix: Update on Mitochondrial Research

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.

Presentation outline, by Richard Frye, MD:
“The Brain Foundation has graciously funded three ongoing projects on mitochondrial function at our center. The first project, a double-blind placebo-controlled crossover trial of a supplement to support mitochondrial function in children with autism spectrum disorder (ASD) who have mitochondrial dysfunction is ongoing but the results are still blinded. So far major findings include the fact that children with ASD have a difficult time ingesting anything that is greater than a small quantity, making the delivery of the powder product challenging. We are working on encapsulating the product to improve delivery to a wide number of children.

The second project examines the effect of treatments on a fibroblast model of mitochondrial dysfunction in ASD. We have found unique changes in mitochondrial function in fibroblasts from children with ASD and modulatory effects of N-Acetyl-Cysteine, Rapamycin and Metformin. The third project involves examining fresh brain in children with and without ASD and/or epilepsy. Unique types of mitochondrial dysfunction are found in different types of epilepsy foci and these changes in mitochondrial function correlate with gene expression data from these regions.

Ongoing studies will correlate mitochondrial function with high-frequency oscillations and examine mitochondrial and gene expression differences between those with and without ASD.”

Edward Quadros, PhD, Professor, Department of Cell Biology, SUNY Downstate Health Sciences University: Folates, Folate Receptor Autoantibodies and the Connection to ASD

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.

Dr. Quadros has established a strong link between an autoimmune disorder that produces autoantibodies against the folate receptor alpha, a membrane receptor involved in folate transport to the fetus and to the brain. Extensive research in Dr. Quadros’ laboratory is aimed at understanding the cause and effects of this autoimmune disorder and how best to prevent and treat the pathologic consequences.

Dr. Quadros holds a BSc in Chemistry from the University of Poona, a MSc in Applied Biology from the University of Bombay and a PhD in Biochemistry from the University of London.

Harris Huberman, MD, Professor of Pediatrics, The Children’s Hospital at SUNY Downstate: Folate Autoantibody Trajectories & ASD Identification in Early Childhood

Harris Huberman, MD, is a developmental pediatrician and the director of the SUNY Downstate Division of Child Development. He was the Medical Director of the NYC Infant Child Health Assessment Program – NYC’s Early Intervention Child Find program and has been the PI of several NIH and MCHB-funded studies of interventions to improve early child development. Currently he is the PI on two clinical trials to treat young children with ASD with leucovorin in collaboration with Phoenix Children’s Hospital, and is the PD of the newly formed Brooklyn Leadership Education in Neurodisabilities (LEND) program funded by MCHB. Dr. Huberman’s areas of interest include: autism, public health and its intersection with child development, preventive parenting programs to improve developmental outcomes for children living in poverty, international health.

Dr. Huberman currently directs the Behavior and Development rotation for Downstate’s pediatric residents and with his team runs a Child Development clinic which is heavily focused on identifying and caring for children on the Autism Spectrum.

T. Atilla Ceranoglu, MD, 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

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable presentation of difficulties with socialization, reciprocal communication, and restrictive/repetitive behaviors. Currently, there exists no approved treatments for core features of ASD. Transcranial Photobiomodulation (tPBM) is a novel treatment approach based on application of an invisible, non-ionizing electromagnetic wave that results in metabolic modulation in tissues targeted. A recent, prospective, 8-week open-label treatment trial in adult patients with ASD revealed that tPBM was well tolerated and was effective in reducing symptom severity of ASD. In addition, tPBM treatment was associated with improvements in executive functions. Presently, an 8-week, prospective, placebo (sham) controlled, double-blind randomized clinical trial to evaluate the efficacy, safety, and tolerability of tPBM with near-infrared light in intellectually capable adults with ASD is underway. Up to 36 participants will be randomized at 1:1 ratio to receive daily tPBM or sham treatments for 8 weeks. The participants will be assessed on measures of efficacy and safety at regular scheduled visits throughout the study. A responder will be defined as those with a ≥25% reduction in Social Responsiveness Scale-2nd Edition, and a score of 2 or 1 on the Clinical Global Impression of ASD Improvement Subscale.

Karen Parker, PhD, Associate Professor of Psychiatry and Behavioral Sciences, Stanford University: Vasopressin: A promising Neurochemical Marker and Therapeutic for Autism

Autism spectrum disorder (ASD) is currently diagnosed behaviorally because its pathophysiology remains poorly understood. Consequently, there are no laboratory-based diagnostic tests to detect ASD and no disease-modifying medications to treat its core behavioral features. The capability of rapidly detecting ASD based on neurochemical markers, however, would revolutionize ASD detection, enable more timely behavioral intervention, and provide targets for pharmacological treatment. To address these urgent unmet clinical needs, we developed a translational ASD research program, spanning studies of naturally low-social monkeys to children with ASD. Converging evidence from this body of research indicates that the neuropeptide vasopressin plays a critical and conserved role in regulating social abilities, and that brain vasopressin signaling is impaired in low-social monkeys, children with ASD, and newborn infants before the period when ASD first manifests. On the basis of this compelling evidence, we recently conducted a first-in-class double-blind, randomized, placebo-controlled pilot trial. We found that intranasal vasopressin treatment is well tolerated and significantly improves social abilities in children with ASD. These findings suggest that a neurochemical marker of impaired social functioning may be present very early in life, before behavioral symptoms emerge, and that the vasopressin signaling pathway may hold diagnostic and therapeutic promise for ASD.

Randy Blakely, PhD, Executive Director, Stiles-Nicholson Brain Institute and Florida Atlantic University College of Medicine: Bidirectional Neuroinflammatory and Serotonin Signaling – Basic and Translational Perspectives

Sixty years ago, Schain and Freedman reported elevated serotonin (5-HT) in the blood of individuals with autism, a finding well-substantiated but still of enigmatic significance. We and others have shown using genetic and biochemical approaches that blood and CNS 5-HT levels are not directly related, raising questions as to whether changes in molecular pathways common to the regulation of brain and peripheral 5-HT synthesis, signaling and/or inactivation may link hyperserotonemia to ASD. We identified multiple, rare coding variants in the antidepressant 5-HT transporter (SERT, SLC6A4) in ASD multiplex families, each displaying hyperactivity. Expression of one of these substitutions (Gly56Ala) in transgenic mice leads to hyperserotonemia, elevated CNS 5-HT clearance, changes in pup vocalizations and adult social behavior, and repetitive behavior. These studies reinforced our efforts to understand how SERT activity is normally enhanced, leading to the discovery that SERT can be rapidly activated by the inflammatory cytokine IL-1beta (and TNFalpha), whose receptor (IL-1R1) is highly expressed by CNS 5-HT neurons. Moreover, SERT Ala56 mice display elevated expression of pro-inflammatory cytokines in the CNS and periphery, supporting a bidirectional link between the innate immune system and 5-HT signaling that may induce specific and reversible ASD traits and/or ASD comorbidities.

Aurelio Galli, PhD, DSc, Director for Gastrointestinal Biology Research,
University of Alabama at Birmingham: Watch Flies Teaching Us Mechanisms of Neuropsychiatric Disorders

The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders including autism spectrum disorder (ASD). We investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N336). We uncovered that the deletion promoted an unobserved conformation of the intracellular gate of the transporter, likely representing the rate limiting step of the transport process. It is defined by a “half-open and inward facing” state (HOIF) of the intracellular gate that is stabilized by a network of interactions conserved phylogenetically, as we demonstrated it both in hDAT by Rosetta molecular modeling and fine grained simulations as well as in its bacterial homolog leucine transporter by EPR analysis and X-ray crystallography. The stabilization of the HOIF state is associated with both DA dysfunctions demonstrated in isolated brains of Drosophila melanogaster expressing hDAT ∆N336 and with abnormal behaviors observed at high-time resolution. These flies display increased fear, impaired social interactions, and locomotion traits we associate with DA dysfunction and the HOIF state. Our results describe how a genetic variation causes DA dysfunction and abnormal behaviors by stabilizing a HOIF state of hDAT.

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

This is a progress report of the research project funded by the Brain Foundation.
Aim 1 Determine the state of innate immune memory (IIM) in the ASD subjects with the use of peripheral blood monocytes (PBMCs).
In initial screening of histone modification markers in purified PBMCs, we found the most significant changes in expression of H3K27ac. Unlike animal models of IIM, H3K27ac tended to be up-regulated in ASD PBMCs at high frequency. We are in the process of conducting super-enhancer CHIP sequencing using H3K27ac as a target molecule in the 1st 12 samples that include ASD subjects with or without up-regulated H3K27ac. These results will be correlated with functional assay results of monocytes.
Aim 2 Determine the feasibility of circulatory 7 miRNAs selected as the biomarkers of neuroinflammation. Seven circulating miRNAs selected based on our previous study were measured by qRT-PCR in 200 samples from both ASD and non-ASD subjects. In ASD subjects with sleep/seizure disorders had low circulatory levels of the miRNAs and did not reveal close associations with monocyte cytokine profiles. In contrast, ASD subjects without sleep/seizure disorders tended to have higher levels of these miRNA with negative associations with monocyte cytokine production.

Sarkis Mazmanian, PhD, Luis B. and Nelly Soux Professor of Microbiology, California Institute of Technology: Gene-Microbiome Interactions in an ASD Mouse Model

Individuals with autism spectrum disorder (ASD) 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.

Joseph Buxbaum, PhD, Professor of Psychiatry, Neuroscience, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai: Connecting Rare Genetic Mutations in ASD to Common Biological Pathways

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.

Stuart Lipton, MD, PhD, Hannah and Eugene Step Chair; Professor; Co-director, Neuroscience Translational Center Department of Molecular Medicine, The Scripps Research Institute: Potential of MEF2 Transcriptional Activator to Improve ASD Phenotypes
Stuart Lipton is best known for first describing the mechanism of action and contributing to the clinical development of the FDA-approved Alzheimer’s drug, memantine & for discovering the posttranslational redox modification known as protein S-nitrosylation. Recently, Lipton and colleagues combined memantine with S-nitrosylation chemistry to produce a new drug called NitroSynapsin, which displays disease-modifying activity in animal models of Alzheimer’s disease, both protecting synapses & improving neurobehavioral deficits.

Lipton’s group also characterized HIV-related pathways to neuronal damage, discovered the NR3 family of modulatory NMDA-type glutamate receptor subunits in the brain, characterized the molecular pathways for protecting neurons with Erythropoietin, & discovered the transcription factor MEF2C. His group showed that MEF2C activity is regulated by S-nitrosylation & serves as a master switch for neurogenesis from human neural stem cells. Dysregulated MEF2C is involved in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, Autism-Spectrum Disorder, and Vascular dementia.
Ongoing research in the lab is focused on 2D human induced pluripotent stem cell (hiPSC)-derived cultures and 3D cerebral organoid models of neurodegenerative and neurodevelopmental disease and aberrant redox/S-nitrosylation pathways leading to synaptic damage.

Using these approaches, the Lipton group is developing novel drugs to combat Alzheimer’s disease, Parkinson’s disease, Vascular dementia (VaD), and other neurodegenerative disorders, as well as Autism-Spectrum Disorder and Intellectual and Developmental Disabilities. Tissue culture models complement whole-animal approaches. A plethora of techniques is employed, including chemical biology, molecular biology, patch-clamp electrophysiology, calcium imaging, and neurobehavioral paradigms.

Kazue Takahashi, PhD, Assistant Professor, Department of Radiology, Gordon Center for Medical Imaging, Harvard Medical School: Mannose Binding lectin in Health and Diseases

MBL (mannose-binding lectin) is a pattern recognition molecule and a component of innate immunity, the first line of the host defense system against pathogens, foreign bodies, altered self, and excess amounts of own molecules. MBL deficiency is common in humans, and it was initially identified as a risk factor among children with recurrent infections. We have generated mouse models of MBL deficiency in order to confirm clinical findings, in particular infectious diseases. Unexpectedly, these model studies have uncovered novel roles of MBL and evidence of its interaction with other molecules of the innate immune system. More recently, hyper-MBL levels in plasma have been identified and associated with diseases. At last, MBL is a disease modifier and that MBL imbalance (hypo-, hyper, dysfunction) affects underlying disease conditions, including metabolic diseases.

Paul Ashwood, PhD, Professor, Department of Medical Microbiology and Immunology, University of California, Davis: Gastrointestinal Immune Dysfunction in Autism

Paul Ashwood, PhD, 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.

Arthur Krigsman, MD, Pediatric Gastroenterologist, Private Practice New York, and Steve 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

Arthur Krigsman, MD, is a pediatrician and pediatric gastroenterologist with expertise in the evaluation & treatment of autism associated GI 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 GI problems. His research interest lies in the characterization of the unique cellular, molecular & clinical features of ASD-associated IBD and his original findings appear in numerous peer-reviewed journals. In addition to serving as an invited reviewer for peer-reviewed medical journals, Dr. Krigsman has served as a guest lecturer on the topic of GI 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 GI disease in this vulnerable population.

Stephen Walker, PhD, is a Professor of Regenerative Medicine at the Wake Forest School of Medicine, Winston- Salem, NC. He received his PhD in Genetics and Developmental Biology and was a Post-Doctoral Fellow in the Molecular Genetics Program at Wake Forest School of Medicine prior to joining the Department of Pediatrics faculty in the Section on Medical Genetics. One focus of his laboratory is the application of integrated multi-omics approaches and clinical data to understand the molecular basis for chronic gastrointestinal symptoms in children with an ASD diagnosis, and to understand how chronic GI problems early in childhood may impact neurodevelopment.

Alessio Fasano, MD PhD, Center for Celiac Research and Treatment; Director, Mucosal Immunology and Biology Research Center & Marcy Kingsbury, PhD, Assistant Professor of Pediatrics, Massachusetts General Hospital/Harvard Medical School: Using a Humanized Mouse Model And Human Intestinal Tissue to Evaluate the Zonulin Pathway For Personalized Treatment of ASD

Autism spectrum disorder (ASD) is a heterogeneous and complex neurodevelopmental disorder that affects social communication and behavior. Many children with ASD also have gastrointestinal (GI) symptoms and dysfunction. However, whether these GI comorbidites contribute to the core behavioral hallmarks of ASD remains unknown. Pre-haptoglobin-2 protein (pre-HP2) is the archetype of the zonluin family that reversably regulates barrier permeability by modulating intercellular tight-junctions. Clinical studies have reported increased intestinal permeability and elevated serum zonulin in ASD patients. Moreover, an imbalance in gut microbes triggers zonulin release, increasing gut permeability, antigen trafficking, and inflammation. Zonulin release can also increase blood-brain-barrier (BBB) permeability, triggering neuroinflammation. Importantly, ASD patients show changes in the diversity and composition of their gut bacteria. However, it is unknown whether their altered gut microbiota acts through the zonulin pathway to exacerbate behavioral symptoms. We are using zonulin-expressing transgenic mice (characterized by increased intestinal permeability), human gut organoids obtained from ASD children, and the zonulin antagonist AT1001, to determine whether a genetic predisposition for increased intestinal permeability (HP2-2 genotype) interacts with ASD gut microbiota to induce “leaky” gut and blood-brain barriers (BBB) and behavioral deficits. We intend to generate robust pre-clinical data leading to innovative targeted ASD treatments.

Robert K. Naviaux, MD, PhD, Professor of Genetics, Biochemical Genetics and Metabolism, Departments of Medicine, Pediatrics, and Pathology Co-director, The Mitochondrial and Metabolic Disease Center (MMDC) UCSD School of Medicine: Emerging Therapeutics for ASD—Shifting Paradigms and Improving Outcomes with Mitochondrial Cell Danger Response (CDR) and Healing Cycle Research

Broad-spectrum metabolomic and exposomic analyses were conducted in 4 independent cohorts of autism spectrum disorder (ASD). These results were compared to 12 other chronic complex disorders using machine learning techniques. Over 30 biochemical pathways were dysregulated in ASD. A core set of about 20 metabolic pathways was shared with ASD and coordinately dysregulated in every chronic complex disorder studied. These core pathways defined the cell danger response (CDR), which we found to persist abnormally and block healing in each disorder. Three programmed transformations in mitochondrial function, designated M1, M0, and M3, were required to progress from inflammation, to proliferation, and remodeling—the 3 stages of healing. Promising clinical trial results from Paxmedica using the drug suramin, and Jelikalite using transcranial optodynamic therapy (ODT) have recently been reported. In addition, a third promising approach using ATP efflux inhibition by pannexin channel blocking drugs being developed by Pannex Therapeutics may prove to be synergistic with the other approaches. Each of these three new approaches acts to restore normal mitochondrial dynamics needed for progress through the molecular stages of the healing cycle. These restore a more normal microbiome, autonomic nervous system balance, neuroendocrine signaling, improve sleep, and dozens of other neurotransmitter, chemical, and synaptic abnormalities present in ASD.
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.
Tom Geraci, D.O. Board Certified Emergency Medicine Physician

Synchrony 2021 Industry Talks

Neil Littman, Founder and CEO, Bioverge Inc.: Democratizing Access to Early-stage Healthcare Investments

Neil Littman, MS, is Founder & CEO of Bioverge, a venture capital firm exclusively dedicated to investing in early-stage, cutting-edge healthcare companies. Bioverge’s investment thesis is focused on companies spanning the intersection of health + tech that are utilizing advances in technology to modernize healthcare, from bench-to-bedside.

Previously, Neil was Vice President of Business Development at Notable Labs, an oncology startup and Bioverge portfolio company, where he led the development of global corporate partnerships and contributed to the strategic vision of Notable as part of the Senior Leadership Team. Neil oversaw business development at Notable through the successful completion of the company’s $40 million Series B. Previously, Neil was a member of the Executive Leadership Team and Director of Business Development at the California Institute for Regenerative Medicine.
Prior to CIRM, Neil was a healthcare investment banker at Thomas Weisel Partners and Deutsche Bank and worked on transactions totaling over $1 billion. His primary focus was on strategic advisory and  public and private financings. Neil received a Master of Science in Biotechnology from The Johns Hopkins University.

Bioverge is an investment platform and syndicate that connects individual investors with highly curated investment opportunities at the intersection of health + tech (or TechBio): “We help our members invest in the health-related causes they care about most and we help companies bridge the valley of death. At Bioverge, we believe we can all do well by doing good.”

John Slattery, Co-founder, President, and CEO, BioROSA: Metabolic Autism Prediction (MAP) Study: A multicenter prospective double-blind case/control study assessing metabolic prediction of ASD from a developmental pediatrics waitlist

Prior to founding BioROSA, John Slattery worked in academia doing ASD clinical and translational research at Arkansas Children’s Hospital from 2010-2017 with Drs. Richard Frye, Jill James, Stephen Kahler, Shannon Rose, and others. As a part of a multidisciplinary autism research group focused on novel therapeutic strategies for ASD, along with biomarker discovery work on putative etiological and pathophysiological factors underlying ASD, John was involved in over 35 highly cited peer reviewed articles on ASD dedicated to this work. The ACH team’s most significant achievement at the time was conducting one of the only positive Phase 2 clinical trials that investigated a novel intervention in autism which was billed “the first positive precision medicine initiative in neuropsychiatry”.

John has extensive ties to the autism clinical, research, and patient community and a wide knowledge base of ASD from a clinical, scientific, and business perspective. At ACH John was the personnel manager for the autism program and managed a team of 10 and was the director of autism translational research under Dr. Richard Frye, MD/PhD. John joined a software startup company in 2017 where he was in charge of sales and R&D. Prior to that he worked at UPenn doing brain imaging research from 2007-2010. John has a BA from the University of Arkansas and has multiple certifications in clinical research.

In this talk John Slatter gave an update on their ongoing clinical trial for metabolic prediction of autism using BioROSA developed laboratory methods

Stephen O’Quinn, PharmD, Vice President, Medical Affairs, Zynerba Pharmaceuticals: ZYN002 Cannabidiol Transdermal Gel Efficacy and Safety – Recent Clinical Research Advances in the Treatment of Autism and Fragile X Syndrome

ZYN002 is a pharmaceutically produced cannabidiol transdermal gel in development for the treatment of behavioral symptoms associated with autism spectrum disorder (ASD) and Fragile X Syndrome (FXS). FXS is the most common monogenic cause of ASD. The results of recently completed trials evaluating the safety and efficacy of ZYN002 in ASD and FXS will be discussed. The design of a new Phase 3 trial in FXS, RECONNECT, will also be reviewed. Data suggest that ZYN002 is well tolerated in children and adolescents age 3 through 17 years. The most common treatment-related adverse event in patients receiving ZYN002 has been application site pain; occurring in less than 7% of patients and generally mild in severity. There have been no reports of significant laboratory changes, including liver function. Open-label efficacy data in ASD suggest ZYN002 may improve behavioral symptoms of ASD, including irritability, social withdrawal and anxiety, as well as some core symptoms of ASD. Controlled clinical trials in ASD are warranted to confirm these effects. Data also demonstrate short-term and longer-term improvements in social avoidance in FXS in patients with complete or near complete methylation of the FMR1 gene. The RECONNECT trial is planned to confirm results in patients with FXS.

Eugene Prahin, CFO, Yamo Pharmaceuticals: L1-79 for Treatment of Core Symptoms of Autism

Yamo proposes L1-79, a racemic mixture of DL-alpha Methyltyrosine e (DL­AMPT) for the treatment of the core deficits in social communication and interaction in adolescents and young adults with the autism spectrum disorder (ASD). L1-79 is a tyrosine hydroxylase inhibitor known to decrease catecholamine biosynthesis by inhibiting the conversion of tyrosine to dihydroxy-phenylalanine (DOPA), the rate limiting step in catecholamine synthesis. L1-79 reduces the imbalance in the catecholaminergic system in a broad way that cannot be mimicked by selective receptor blockers (e.g.; risperidone and aripiprazole) or lytic enzyme measures. Unlike dopamine receptor antagonists, whose targets are predominantly limited to more specific (and potentially less relevant) subtypes of central dopaminergic activity, L1-79’s catecholamine-based mechanism of action (MOA) is the first therapy based on a rationale that allows for a more expansive theory of ASD. By taking a broader spectrum approach in modulating multiple neurotransmitter systems that play a key role in social communication, interaction as well as autonomic function, L1-79 has the potential to improve the core symptoms of autism underlying the condition.

Colleen Kraft, MD, MBA, FAAP, Senior Medical Director, Clinical Adoption, Cognoa and Professor of Pediatrics, Keck School of Medicine, University of Southern California: Streamlining the Current Autism Diagnostic Pathway

Lack of diagnostic tools for Autism Spectrum Disorder (ASD) in primary care settings and long wait lists for specialist assessment contribute to an average delay of 3 years between first parental concern and diagnosis. This prospective multi-site double-blind active comparator study compared the performance of an artificial intelligence-based device intended to aid primary care providers (PCPs) diagnose ASD, to specialist clinician diagnosis. Participants were 18-72-month-olds with developmental delay concern (425 completers). Comparison of device results to specialist diagnosis found the PPV: 80.8%, NPV: 98.3%, sensitivity: 98.4%, specificity: 78.9% for subjects with determinate device results. Device use could potentially expand timely, accurate and equitable ASD diagnosis in primary care.

C.E.O., Sirica Therapeutics: Sirica Therapeutics – Making Therapy Fun!

Autism spectrum disorder diagnoses are accelerating. Currently, behavioral therapy services are being strained. There is a growing demand that cannot be met in the future. The pandemic has shown that the traditional model of having the therapists do one on one sessions is harder due to the constraints of social distancing, vaccination requirements and wearing of masks. There is also the problem of inconsistent data, coming in slowly from these sessions to make quick, meaningful changes that will improve patient outcomes.
We are building a therapeutic device by putting together a combination of technologies namely, robotics, virtual reality and machine learning that can solve some of the biggest challenges faced by this population. This device will use physical, mental and psychological tools to help create a program to calm behaviors, improve achievement and enhance neuroplasticity. Several thousand data points will be collected automatically and are stored in the cloud. Machine learning algorithms can make changes to the program very quickly. It can generate automatic progress reports. A therapist could run a few machines simultaneously while in the clinic or even remotely from a patient’s home. It will be designed to be an adjunct to the one on one therapy.

Stewart Campbell, Ph.D., CEO Axial Biotherapeutics: Targeting bacterial metabolites as a strategy to manage irritability associated with autism

Stewart Campbell, PhD, 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.

James N. Woody, MD PhD, CEO, MARAbiosystems: MaraBio, a Precision Medicine ASD diagnostic Company

Mara Biosystems is an early-stage ASD precision medicine diagnostic and therapeutic company. The technology is based on the decade long work of Dr. Judy Van de Water, of the UC Davis Mind Institute who discovered that the cause of a subset of autism was that 15-25% % of mothers with ASD children, had maternal antibodies directed against eight infant brain proteins. These maternal antibodies can cross the placental barrier at about day 100 and damage the child’s brain in utero. Our test detects these antibodies in mothers. The initial use will be in families that have a child who has missed developmental milestones, has a positive M- Chat etc., even before definitive symptoms develop. The test can provide actionable information If the mother has MARA (Maternal Autism Related Autoantibodies) as the child is likely to be autistic and can enter earliest interventional therapy for the best outcomes. We have performed retrospective and prospective studies with over 1000 samples analyzed. Future indications include mothers with a prior ASD child, contemplating having another child., if MARA positive can provide risk. The company will not be testing pregnant women at this time but has a potential therapeutic to eliminate such antibodies.

Erik Won, President & Chief Medical Officer, Wave Neuroscience: Biometric-Guided TMS for Kleefstra Syndrome

Kleefstra syndrome is a rare genetic condition that affects development and involves many body systems. Children with Kleefstra syndrome exhibit features of autism, developmental delay, communication difficulties, and low muscle tone (hypotonia). The condition is caused by a mutation in a gene called EHMT1 or the deletion of a specific region of chromosome 9 that includes EHMT1. Biometric-Guided TMS has shown some early promise in the treatment of Autism Spectrum Disorder (ASD), and based on the success of a Kleefstra Syndrome case there are plans to conduct a collaborative clinical trial between Wave Neuroscience, Boston Children’s Hospital, Radboud University Nijmegen Medical Centre (Netherlands), and iDefine (501c3). This session will review scientific principles of the treatment approach, clinical outcomes, and the firsthand experience of a physician who is also the parent of a child with Kleefstra Syndrome.
Eugenia Steinhold PhD, Chief Scientific Officer, JelikaLite Corp.: tPBM May Reduce Symptoms of Autism as Measured by Behavioral Change and EEG
Transcranial Photobiomodulation (tPBM) May Reduce Symptoms of Autism, as measured by Behavioral Change and EEG – a presentation by Eugenia Steingold, PhD, a pediatric psychologist, who has been working with children on the Autism Spectrum for the last 15 years. She completed her doctoral studies in Cognitive Psychology at Princeton University, followed by postdoctoral fellowship in the Laboratory for Developmental Studies at Harvard University. Her original research focused on Language Acquisition and Processing. Her research projects have been sponsored by NIH and NSF.

Her current research and clinical interests include Autism, Language Delays, Developmental Delays, Cognition, and neurological and psychological response to trauma.

During the last two years, as a CSO of Jelikalite, she has been working on developing and validating tPBM technology for treating Autism in young children.

Synchrony provides hope to autism parents and family who has tried many different interventions and still searching for answers to help their children and dear ones impacted by autism
Parul Agrawal PhD, Parent

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