Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an equally ample effort to employ clinical studies for studying the ASD causes and cell therapies. Stem cells have yielded so far mixed results in clinical trials, and at patient level the results varied from impressive to no improvement. In this context we have administered autologous cord blood (ACB) and a non-placebo, material intervention represented by an individualized combination of supplements (ICS) to ASD children.

To compare the efficacy of ACB vs ICS and find markers correlated with the child's progress in order to better predict ACB efficacy.

CORDUS clinical study is a crossover study in which both oral ICS and intravenous ACB were sequentially administered to 56 children; ACB was infused as an inpatient procedure. Treatment efficacy was evaluated pre-treatment and post-treatment at 6 months by an independent psychotherapist with Autism Treatment Evaluation Checklist, Quantitative Checklist for Autism in Toddlers and a 16-item comparative table score, after interviewing the children’s parents and therapists. Before and after each intervention participants had a set of blood tests including inflammatory, metabolic and oxidative markers, and the neuronal specific enolase.

No serious adverse reactions were noted during and after cord blood or supplement administration. ACB improved evaluation scores in 78% of children with age 3–7-years (n = 28), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n = 28; only 11% of children improved scores). ICS yielded better results than ACB in 5 cases out of 28, while in 23 kids ACB brought more improvement than ICS (P < 0.05); high initial levels of inflammation and ferritin were associated with no improvement. Ample individual differences were noted in children's progress, and statistically significant improvements were seen after ACB on areas such as verbalization and social interaction, but not on irritability or aggressive behavior.

ACB has superior efficacy to ICS in ASD; high inflammation, ferritin, age and body weight predict less improvement; more clinical studies are needed for studying ACB efficacy in ASD.

• Autistic spectrum disorder
• Cord blood
• Stem cells
• Neuroinflammation
• Autologous stem cell treatment
• Neuronal specific enolase

• autism spectrum disorder
• bipolar disorder
• major depression
• schizophrenia
• treatment-resistant depression

• HUCBCs
• autism
• cell therapy
• children disorders
• treatment

• autism
• children
• evidence-based
• intervention
• stem cells
• treatment

• autism
• autism biomarker
• autistic spectrum disease (ASD)
• mTOR
• neuroinflammation
• neuron-specific enolase (NSE)
• neuronal apoptosis

• Autism
• Bumetanide
• EEG
• Excitation-inhibition
• Machine learning
• RCT
• Repetitive behavior

• ASD animal model
• autism spectrum disorder (ASD)
• neurobiological mechanisms
• neurocircuit mechanisms
• therapeutic strategies

• Animals
• Autism Spectrum Disorder/genetics
• Autism Spectrum Disorder/therapy
• Autistic Disorder/genetics
• Risk Factors
• Inflammation
• Biological Factors/therapeutic use

Autism spectrum disorder (ASD) represents a set of heterogeneous neurodevelopmental conditions defined by impaired social interactions and repetitive behaviors. The number of reported cases has increased over the past decades, and ASD is now a major public health burden. So far, only treatments to alleviate symptoms are available, with still unmet need for an effective disease treatment to reduce ASD core symptoms. Genetic predisposition alone can only explain a small fraction of the ASD cases. It has been reported that environmental factors interacting with specific inter-individual genetic background may induce immune dysfunctions and contribute to the incidence of ASD. Such dysfunctions can be observed at the central level, with increased microglial cells and activation in ASD brains or in the peripheral blood, as reflected by high circulating levels of pro-inflammatory cytokines, abnormal activation of T-cell subsets, presence of auto-antibodies and of dysregulated microbiota profiles. Altogether, the dysfunction of immune processes may result from immunogenetically-determined inefficient immune responses against a given challenge followed by chronic inflammation and autoimmunity. In this context, immunomodulatory therapies might offer a valid therapeutic option. Mesenchymal stromal cells (MSC) immunoregulatory and immunosuppressive properties constitute a strong rationale for their use to improve ASD clinical symptoms. In vitro studies and pre-clinical models have shown that MSC can induce synapse formation and enhance synaptic function with consequent improvement of ASD-like symptoms in mice. In addition, two preliminary human trials based on the infusion of cord blood-derived MSC showed the safety and tolerability of the procedure in children with ASD and reported promising clinical improvement of core symptoms. We review herein the immune dysfunctions associated with ASD provided, the rationale for using MSC to treat patients with ASD and summarize the current available studies addressing this subject.

• Autism
• Autistic disorder
• Meta-analysis
• Stem cell transplantation
• Stem cells
• Systematic review

• Attention
• Autism
• Computer vision
• Gaze-tracking
• Off-the-shelf cameras
• Stimuli design

• P50 HD093074 NICHD NIH HHS
• R01 MH120093 NIMH NIH HHS
• R01 MH122370 NIMH NIH HHS

• Autism
• Biomarkers
• Children
• Clinical trials
• Drug development
• Endpoints
• Treatment

• Autism Spectrum Disorder/drug therapy
• Autism Spectrum Disorder/genetics
• Biomarkers
• Communication
• Drug Development
• Humans
• Phenotype

• P50 HD055784 NICHD NIH HHS
• P50 HD093074 NICHD NIH HHS
• P50 HD103557 NICHD NIH HHS

• clinical trials
• ethics
• mesenchymal stem cells (MSCs)
• stem cells
• umbilical cord

• Clinical Trials as Topic
• Conflict of Interest
• Disclosure
• Editorial Policies
• Humans
• Patient Participation/economics
• Stem Cells
• Translational Science, Biomedical

• autism
• computer vision
• early detection
• facial expressions
• risk behaviors

• Area Under Curve
• Autism Spectrum Disorder/diagnosis
• Autistic Disorder/diagnosis
• Child, Preschool
• Facial Expression
• Family
• Female
• Humans
• Infant
• Male
• Movement
• Phenotype
• ROC Curve

• P50 HD093074 NICHD NIH HHS
• R01 MH120093 NIMH NIH HHS
• R01 MH121329 NIMH NIH HHS
• R01 MH122370 NIMH NIH HHS

Ollivier–Ricci curvature is a method for measuring the robustness of connections in a network. In this work, we use curvature to measure changes in robustness of brain networks in children with autism spectrum disorder (ASD). In an open label clinical trials, participants with ASD were administered a single infusion of autologous umbilical cord blood and, as part of their clinical outcome measures, were imaged with diffusion MRI before and after the infusion. By using Ricci curvature to measure changes in robustness, we quantified both local and global changes in the brain networks and their potential relationship with the infusion. Our results find changes in the curvature of the connections between regions associated with ASD that were not detected via traditional brain network analysis.

• diagnostic markers
• autism spectrum disorders

• Attention/physiology
• Autism Spectrum Disorder/physiopathology
• Autism Spectrum Disorder/psychology
• Brain/physiopathology
• Child
• Child, Preschool
• Electroencephalography
• Feasibility Studies
• Female
• Humans
• Male
• Neurologic Examination/methods
• Social Behavior
• Time Factors

• P50 HD093074 NICHD NIH HHS
• R01 MH120093 NIMH NIH HHS
• R01 MH121329 NIMH NIH HHS
• NIH Autism Center of Excellence Award (NICHD P50HD093074), NSF, SFARI, gifts from Amazon, Google, Cisco, Microsoft
• NIH Autism Center of Excellence Award (NICHD P50HD093074), NSF, DoD, SFARI, gifts from Amazon, Google, Cisco, Microsoft

• Autism spectrum disorders
• Neuro inflammation
• Neurological disorders
• Regenerative medicine
• Stem cell therapy

• Animals
• Autism Spectrum Disorder/genetics
• Autism Spectrum Disorder/therapy
• Autistic Disorder
• Child
• Forecasting
• Humans
• Stem Cell Transplantation

• Autism spectrum disorder
• Dietary supplementations
• Exclusion diets
• Non-Pharmacological strategies
• Pharmacological interventions
• Stem cell therapies

Autism and autism spectrum disorders (ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD. Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review will focus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.

• Autism spectrum disorders
• Mesenchymal stem cells
• Major histocompatibility complex
• Inflammation
• Maternal immune activation
• Cell therapy

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by social communication deficits and the presence of restricted interests and repetitive behaviors. We have previously reported significant improvements in behavior, including increased social functioning, improved communication abilities, and decreased clinical symptoms in children with ASD, following treatment with a single infusion of autologous cord blood in a phase I open‐label trial. In the current study, we aimed to understand whether these improvements were associated with concurrent changes in brain structural connectivity. Twenty‐five 2‐ to 6‐year‐old children with ASD participated in this trial. Clinical outcome measures included the Vineland Adaptive Behavior Scales‐II Socialization Subscale, Expressive One‐Word Picture Vocabulary Test‐4, and the Clinical Global Impression‐Improvement Scale. Structural connectivity was measured at baseline and at 6 months in a subset of 19 children with 25‐direction diffusion tensor imaging and deterministic tractography. Behavioral improvements were associated with increased white matter connectivity in frontal, temporal, and subcortical regions (hippocampus and basal ganglia) that have been previously shown to show anatomical, connectivity, and functional abnormalities in ASD. The current results suggest that improvements in social communication skills and a reduction in symptoms in children with ASD following treatment with autologous cord blood infusion were associated with increased structural connectivity in brain networks supporting social, communication, and language abilities. stem cells translational medicine2019;8:138&10

• Autism spectrum disorder
• Autologous umbilical cord blood
• Diffusion tensor imaging
• White matter connectivity