Abstract
Neurodevelopmental disorders represent a challenging biological and medical problem due to their genetic and phenotypic complexity. In many cases, we lack the comprehensive understanding of disease mechanisms necessary for targeted therapeutic development. One key component that could improve both mechanistic understanding and clinical trial design is reliable molecular biomarkers. Presently, no objective biological markers exist to evaluate most neurodevelopmental disorders. Here, we discuss how systems biology and “omic” approaches can address the mechanistic and biomarker limitations in these afflictions. We present heuristic principles for testing the potential of systems biology to identify mechanisms and biomarkers of disease in the example of Rett syndrome, a neurodevelopmental disorder caused by a well-defined monogenic defect in methyl-CpG-binding protein 2 (MECP2). We propose that such an approach can not only aid in monitoring clinical disease severity but also provide a measure of target engagement in clinical trials. By deepening our understanding of the “big picture” of systems biology, this approach could even help generate hypotheses for drug development programs, hopefully resulting in new treatments for these devastating conditions.
Highlights
Rett syndrome is a devastating neurodevelopmental disorder caused by mutations in a gene responsible for both activating and repressing gene transcription: methyl CpG binding protein 2 gene (MECP2; Amir et al, 1999)
After children with Rett syndrome emerge from the regression period, they enter a phase of stability, often with subtle developmental gains or losses, but almost never regain meaningful verbal language or hand use (Downs et al, 2010)
In the case of specific examples of syndromic autism, the explanation for how a single gene mutation can result in such a complex neurodevelopmental disorder often lies in the complex function of the protein product of the mutated gene; in Rett syndrome, MeCP2 regulates the transcription of a host of genes yet to be identified, which may number over 1,000 (Horvath and Monteggia, 2017)
Summary
Rett syndrome is a devastating neurodevelopmental disorder caused by mutations in a gene responsible for both activating and repressing gene transcription: methyl CpG binding protein 2 gene (MECP2; Amir et al, 1999). A deep understanding of ‘‘omic’’-based molecular phenotypes in Rett syndrome could provide a portfolio of biomarkers suitable for many drug development and clinical trial approaches.
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