Defining Precision Medicine Approaches to Autism Spectrum Disorders: Concepts and Challenges

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.

Adaptive behavior in autism: Minimal clinically important differences on the Vineland‐II

“…Analogously, the MCID estimates reported here may be used to identify subgroups of patients with meaningfully distinct degrees of clinical severity, or to identify biomarkers that index clinically meaningful variation [e.g., Lerer et al, 2008;Marquand, Wolfers, Mennes, Buitelaar, & Beckmann, 2016]. Vineland MCID estimates may, therefore, play a broader role, enabling more personalized and biologically informed treatments for ASD (e.g., Loth, Murphy, & Spooren, 2016).…”

Neurobiological bases of autism–epilepsy comorbidity: a focus on excitation/inhibition imbalance

“…It is interesting to observe that neuroligin‐3 mutants display increased GABAergic transmission and no seizures (Tabuchi et al ., ; Földy et al ., ), whereas Group 3 mice mainly show reduced GABAergic transmission and increased seizure susceptibility (Table ). Finally, in patients, a precision medicine approach (Loth et al ., ) to compare clinical cases of ASD with or without epilepsy might help to identify novel biomarkers and drug targets of ASD–epilepsy comorbidity.…”

Altered structural brain asymmetry in autism spectrum disorder: large-scale analysis via the ENIGMA Consortium

“…Characterizing the neurobiology of ASD may eventually lead to improved diagnosis and clinical subgrouping, and the development of individually targeted treatment programs (3).…”