The Evolving Landscape of Functional Models of Autism Spectrum Disorder.

This review looks at different ways scientists study autism in the laboratory. Traditional methods use animals like mice, but these can't show all the human features of autism. Newer methods use human stem cells from patients to create brain-like models in the lab. These human models might be better for testing treatments that could help individual children with autism.

This review examines the evolution of autism spectrum disorder (ASD) research models, from traditional animal models to cutting-edge human stem cell-based approaches. ASD affects 1-3% of the global population and represents a collection of individually rare disorders, each with genetic variants accounting for less than 1% of cases. While animal models have been valuable for preclinical research, they cannot capture human-specific features like protracted neuronal development. The review highlights how human stem cell models, including 2D cultures and 3D organoids derived from patients' own cells, offer promising alternatives for studying ASD's molecular basis and testing personalized therapeutic interventions during critical developmental windows.

This research direction may lead to more personalized therapeutic approaches by using patient-derived stem cell models to test interventions. The focus on developmental windows suggests treatments may be most effective when applied during critical early development periods.

As a review paper, this study does not present original research data. The discussion of human stem cell models represents emerging technology that requires further validation for clinical translation.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1-3% of the population globally. Owing to its multifactorial origin, complex genetics, and heterogeneity in clinical phenotypes, it is difficult to faithfully model ASD. In essence, ASD is an umbrella term for a group of individually rare disorders, each risk gene accounting for <1% of cases, threaded by a set of overlapping behavioral or molecular phenotypes. Validated behavioral tests are considered a gold standard for ASD diagnosis, and several animal models (rodents, pigs, and non-human primates) have traditionally been used to study its molecular basis.

These models recapitulate the human phenotype to a varying degree and have been indispensable to preclinical research, but they cannot be used to study human-specific features such as protracted neuronal maturation and cell-intrinsic attributes, posing serious limitations to translatability. Human stem cell-based models, both as monolayer 2D cultures and 3D organoids and assembloids, can circumvent these limitations. Generated from a patient's own reprogrammed cells, these can be used for testing therapeutic interventions that are more condition and patient relevant, targeting developmental windows where the intervention would be most effective. We discuss some of these advancements by comparing traditional and recent models of ASD.