Editors' ChoiceAutism

A sneak peek at personalized medicine in autism?

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Science Translational Medicine  27 Jul 2016:
Vol. 8, Issue 349, pp. 349ec119
DOI: 10.1126/scitranslmed.aah4506

Autism spectrum disorder (ASD) is a heterogeneous disorder with many etiologies. Dissecting molecular and cellular mechanisms involved in the disorder has been very challenging. Hence, rational, mechanism-based approaches for drug discovery and development have progressed slowly in the past 20 years. This trend may change with the advent of new methodologies such as those involving induced pluripotent stem cells (iPSCs).

Marchetto et al. collected fibroblasts from eight ASD subjects who were identified by MRI data showing larger-than-normal brain volume when they were toddlers, and five age/gender–matched neurotypical control participants. Their cells were first programmed to form iPSCs and then differentiated into NPCs and neurons. The authors found that the NPCs from ASD individuals were characterized by increased proliferation, as compared with controls. This increased proliferation of NPCs from individuals with ASD was regulated specifically by the Wnt-β-catenin/BRN2 transcriptional cascade. Furthermore, ASD-derived neurons exhibited lower spontaneous activity than control-derived neurons. The authors demonstrated that treatment with insulin growth factor 1 (IGF-1), a medication under investigation in patients with ASD and other neurogenetic disorders, had specific biochemical and functional effects in the ASD-derived NPCs and neurons. When IGF-1 was given to ASD-derived neurons, the spontaneous activity became similar to that of control-derived neurons, suggesting that the deficiency in network connectivity in ASD-derived neurons could be improved by targeting a specific transcriptional cascade.

This study illustrated the possibility of identifying subgroups of ASD subjects who might share common molecular deficits and endophenotypes, as well as the potential prospects of mechanism-based, personalized pharmacologic ASD treatments. The main question for this approach is whether functional improvements observed in iPSCs, NPCs, and derived neurons can be extrapolated to behavioral improvements in individuals with ASD.

M. C. Marchetto et al., Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol. Psychiatry 10.1038/mp.2016.95 (2016). [Abstract]

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