Patient-Derived Stem Cells, Another in vitro Model, or the Missing Link Toward Novel Therapies for Autism Spectrum Disorders?

Abstract

Autism Spectrum Disorders (ASDs) is a multigenic and multifactorial neurodevelopmental group of disorders diagnosed in early childhood, leading to deficits in social interaction, verbal and non-verbal communication and characterized by restricted and repetitive behaviors and interests. To date, genetic, descriptive and mechanistic aspects of the ASDs have been investigated using mouse models and post-mortem brain tissue. More recently, the technology to generate stem cells from patients' samples has brought a new avenue for modeling ASD through 2D and 3D neuronal models that are derived from a patient's own cells, with the goal of building new therapeutic strategies for treating ASDs. This review analyses how studies performed on mouse models and human samples can complement each other, advancing our current knowledge into the pathophysiology of the ASDs. Regardless of the genetic and phenotypic heterogeneities of ASDs, convergent information regarding the molecular and cellular mechanisms involved in these disorders can be extracted from these models. Thus, considering the complexities of these disorders, patient-derived models have immense potential to elucidate molecular deregulations that contributed to the different autistic phenotypes. Through these direct investigations with the human in vitro models, they offer the potential for opening new therapeutic avenues that can be translated into the clinic.

Keywords: autism spectrum disorder; genetics; human induced pluripotent stem cells; post-mortem brain studies; therapeutic strategy.

Figure 1

Scheme of ASD Drug discovery based on Genetic Studies, Post-mortem Brain Studies and Cellular Studies using induced pluripotent stem cells (IPSC) for future personalized treatment. Genetic studies reveal associations to Autism Spectrum Disorders either through candidate genes approach or Genome-wide Association Studies (GWAS), whereas genes mutated in syndromic autism have been identified. Furthermore, copy number variations (CNVs) that potentially lead to either gene disruption or duplication were more recently identified. Studies performed on post-mortem tissue provide information about brain anatomy and development, histology and cellular morphology, besides gene and protein expression profiles. Cellular Studies based on IPSC technology may be employed to generate neurons and other cell types (2D) and brain organoids (3D) using cells from patients. Those IPSC-derived models where used to investigate gene expression profiles and cellular morphology as well as cell signaling, synaptogenesis and electrophysiological properties. Moreover, 3D Studies allow to further investigate cellular migration and interaction during development. Those studies provide convergent information regarding the pathophysiology of the Autism Spectrum Disorders, toward altered mechanisms related to Mitochondria function, Synaptic maturation, Cellular interactions, and neuronal development. IPSC-derived cells are currently used to further investigate those altered functions and constitute human in vitro systems allowing drug screenings for potential targets that could lead to new therapies for ASDs.