Phenotyping, Etiological Factors, and Biomarkers: Toward Precision Medicine in Autism Spectrum Disorders

Abstract

Despite the progress made in understanding the biology of autism spectrum disorder (ASD), effective biological interventions for the core symptoms remain elusive. Because of the etiological heterogeneity of ASD, identification of a "one-size-fits-all" treatment approach will likely continue to be challenging. A meeting was convened at the University of Missouri and the Thompson Center to discuss strategies for stratifying patients with ASD for the purpose of moving toward precision medicine. The "white paper" presented here articulates the challenges involved and provides suggestions for future solutions.

Figure 1.

Outline of suggestions for research progress toward precision medicine. A, One critical initial step is generation of establishment of a map of how etiological factors relate to phenotypes and clinical biomarkers in the clinical setting. With this established, one can identify the biomarkers that are associated with specific causes. Furthermore, one can identify a set of other patients with no known cause that may have common biomarkers with a group with a specific cause, which then allows the possibility of determining whether they have a common pattern of treatment response in subsequent trials, either for domain-specific responses or for more global responses. Numerous efforts at exploring biomarkers are underway across a variety of selected settings. B, To allow animal model translation to the clinical setting, these markers should also be explored across a range of animal models. This will allow future testing of new agents across causes and biomarkers. Ellegood et al. have done this for brain imaging markers across animal models. C, For drugs that have shown promise in a broad range of patients with autism spectrum disorder (ASD), whether derived from a molecular drug development approach or not, large trials to further explore efficacy should be taken as an opportunity for biomarker discovery, an exploratory examination for particular causes or biomarkers as they relate to treatment response. This will allow future targeted trails to confirm these associations. The effects of treatment on the biomarkers will help with understanding of the mechanism, and will also contribute to subsequent animal model studies to further refine the understanding of the mechanism and develop more targeted therapeutics. D, For drugs with a highly plausible link to particular causes or biomarkers (e.g., GABAergic-related biomarkers for drugs targeting the GABAergic system), or drugs with causes or biomarkers associated with treatment response discovered in the above pathway (in C), targeted treatment trails can be explored, with targeted biomarkers, for which the study should have sufficient power to determine salience of the biomarker for the trial outcome. With monitoring of the effect of treatment on biomarkers, this will also allow subsequent animal models to further refine the understanding of the mechanism and develop more targeted therapeutics. E, Similarly, new drugs derived from induced pluripotent stem cells and genetic animal models would be assessed with targeted biomarkers in the trial setting. If the patients without the predicted markers also show a positive treatment response, though, the drug could then be reexplored in the exploratory biomarker setting, described above (in C), and in other etiological animal models, to identify other biomarkers salient to treatment response and to move toward a better understanding of its impact.