Autism

Co-Investigator: Dr. Siniscalco Dario

GENOME ENVIRONMENT MICROBIOME METABOLOME in AUTISM (GEMMA)

GEMMA is the first project to combine a multi-omic approach with robust environmental data to exploit the analysis of the composition and function of the microbiome for personalized treatment and, ultimately, disease interception in infants at risk of Autistic Spectrum Disorders (ASD) .The project provides solid mechanistic evidence of the disease onset and progression in relation to dynamic changes in abnormal gut microbiota causing epigenetic modifications controlling gut barrier and immune functions, based on the in- depth evaluation of 600 infants at risk observed from birth and followed over time. These data will be integrated with pre-clinical studies to mechanistically link human microbiota composition/function with clinical outcome through humanized murine models transplanted with stools obtained from the ASD proband patient of recruited families. The project will support novel personalized prediction (personalized treatment) and disease interception (prevention) approaches that attempt to modulate gut microbiota to re-establish/maintain immune homeostasis. The biomarkers identified in this project will contribute to a better understanding of the pathogenesis of ASD in at-risk children and the possibility to manipulate the microbiota through pre/pro/symbiotic administration for prevention and treatment, a complete paradigm shift in ASD pathogenesis and early intervention.The identification of specific ASD metabolic phenotypes will further aid to define biomarkers that can be used as diagnostic tools and patient stratification models for other conditions in which the interplay between genome, microbiome and metabolic profile has been suspected or proved. Finally, the project will collect biospecimens from a cohort of 600 infants as risk of ASD observed from birth, generating a unique biobank of 16,000+ blood, stool, urine and saliva samples prospectively collected that can be exploited in future multi-omic studies.

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Identification of biomarkers for autism-related subtypes

Autism spectrum disorders (ASDs) are severe heterogeneous neuro-developmental disorders characterized by dysfunctions in social interaction and communication skills, repetitive and stereotypic verbal and non-verbal behaviours. Raised from strictly interactions among epigenetic and environmental factors, ASDs are now recognized as multifactorial diseases. Nowadays, autism pathologies are increasing in incidence and prevalence until to present rates of one in 54 children aged 8 years in the US, according to Center for Disease Control; indeed ASDs are being recognized as an urgent public health problem. ASDs significantly impact on the quality of life for both patients and their families. The estimated total lifetime societal cost of caring for one individual with autism is $3.2 million US dollars. Unfortunately, too often ASDs are underestimated and affected children are poorly addressed. The autism diagnosis is suffering by the lack of a specific biomarker for autism, making these pathologies very difficult to be diagnosed. Indeed, despite many research efforts, currently, there are no biomarkers for an exact ASD diagnosis. The current diagnosis of autism is only based on the evaluation of behaviour and social communication skills. The absence of a specific biomarker renders the diagnosis potentially subjective. The priority for the future of ASD management will be the identification of potential targets for the development of diagnostic and/or therapeutic strategies. Several biochemical pathways are associated with ASDs: oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal impaired permeability and dysbiosis; increased toxic metal burden; immune dysregulation; cytokine over-production; endocannabinoid system dysregulation; neuron-glia cross-talk imbalance.

However, the mechanisms of ASD pathogenesis are still unknown, making the biomarker discovery a very tough process. As spectrum, autism-related pathologies are characterized by a large array of specific conditions that address through several autistic subtypes. The exact identification of every single subtype will help in more appropriate diagnosis and specific therapy.

The aim of this project is the establishment of an in vitro system for autism biomarker discovery. Exact identification of a cellular model of autism will address the management of the autistic disorder through a more targeted therapy.

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