Translational Approaches to Drug Discovery in Autism

Because ASD is a heterogeneous disorder comprising of several etiologies, mechanism-based and rational approaches for both drug discovery and development have gradually progressed in the last 20 years. But this trend might change with the arrival of new methodologies that involve iPSCs, or induced pluripotent stem cells.
Marchetto to al. gathered fibroblasts from 8 ASD subjects, identified by MI data exhibiting bigger-than-normal brain volume when only toddlers, and 5 age/gender-matched neurotypical control participants. Their cells were initially programmed to create iPSCs and then differentiated into NPCs and neurons. The study authors discovered that the NPCs from autistic subjects were characterized by greater proliferation, as compared with controls. The wnt-B-catenin/BRN2 transcriptional cascade regulated the increased proliferation of NPCs from autistic individuals.
In addition, ASD-derived neurons showed lower spontaneous activity than control-derived neurons. Researchers demonstrated that treating with insulin growth factor 1(IGF-1) had certain functional and biochemical effects in the ASD-derived neurons and NPCs. When IGF-1 was administered to ASD-derived neurons, the spontaneous activity grew comparable to that of control-derived neurons, indicating that the deficiency in network connectivity in ASD-derived neurons can be enhanced by targeting a certain transcriptional cascade.
This study showed the possibility that subgroups of autistic subjects can be in fact identified who may share the same or similar molecular endophenotypes and deficits, as well as real prospects of the discovery of customized pharmacologic treatments and drugs for ASD. The chief question for this approach: could functional improvements seen in iPSCs, derived neurons, and NPCs be extrapolated to improvements in behavior in ASD people?
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