Abstract
The tremendous clinical and etiological variability between individuals with autism spectrum disorder (ASD) has made precision medicine the most promising treatment approach. It aims to combine new pathophysiologically based treatments with objective tests (stratification biomarkers) to predict which treatment may be beneficial for a particular person. Here we discuss significant advances and current challenges for this approach: rare monogenic forms of ASD have provided a major breakthrough for the identification of treatment targets by providing a means to trace causal links from a gene to specific molecular alterations and biological pathways. To estimate whether treatment targets thus identified may be useful for larger patient groups we need a better understanding of whether different etiologies (i.e., genetic and environmental risk factors acting at different critical time points) lead to convergent or divergent molecular mechanisms, and how they map onto differences in circuit-level brain and cognitive development, and behavioral symptom profiles. Several recently failed clinical trials with syndromic forms of ASD provide valuable insights into conceptual and methodological issues linked to limitations in the translatability from animal models to humans, placebo effects, and a need for mechanistically plausible, objective outcome measures. To identify stratification biomarkers that enrich participant selection in clinical trials, large-scale multi-modal longitudinal observational studies are underway. Addressing these different factors in the next generation of research studies requires a translatable developmental perspective and multidisciplinary, collaborative efforts, with a commitment to sharing protocols and data, to increase transparency and reproducibility.
Highlights
When parents first receive a diagnosis of autism spectrum disorder (ASD) of their child, some of their most pressing questions are: what is the prognosis of my child? What has caused his/her autism? And what are the treatment options?
In addition to genetic factors, it is likely that environmental influences – notably those acting during the embryonic stage – modulate risk for ASD
In the STX209 arbaclofen trial with volunteers with “idiopathic” ASD, the Aberrant Behavior Checklist (ABC)-irritability subscale was used as the primary outcome measure; again because the measure is known to be sensitive to change in pharmacologic trials
Summary
When parents first receive a diagnosis of autism spectrum disorder (ASD) of their child, some of their most pressing questions are: what is the prognosis of my child? What has caused his/her autism? And what are the treatment options?. IQ and language level are widely considered the best predictors of outcome It is currently largely unknown whether different developmental trajectories may reflect different biological subgroups, and why some individuals develop comorbidities but others do not. Two medications (the second-generation antipsychotics risperidone and aripiprazole) have been approved in ASD by the US Food and Drugs Administration (FDA) and one (risperidone) by the European Medicines Agency (EMA) Both medications are not specific for ASD and target associated symptoms, such as aggression or irritability. The management of ASD relies heavily on behavioral and educational interventions [7] Several of these programs report significant improvements, difficulties in generalizing skills to “real-world” settings, and access to these treatments and their expense, remain common limitations [8]
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