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Drug discovery for autism spectrum disorder: challenges and opportunities

Nature Reviews Drug Discovery volume 12, pages 777–790 (2013)Cite this article

Subjects

Key Points

  • The current prevalence rates of autism spectrum disorder (ASD) are about 1 in a 100, with a greater incidence in boys.

  • ASD has a strong genetic component, and new sequencing methods have allowed the identification of many rare and de novo mutations that can contribute to the condition.

  • Many of the genes associated with ASD encode for proteins that act at the synapse, which suggests that these might be potential points of intervention and therapeutic targets.

  • Induced pluripotent stem cells derived from individuals with ASD and animal models with construct and face validity provide an opportunity to identify cellular and molecular phenotypes associated with the condition.

  • Clinical development of therapeutics for ASD poses particular challenges with regard to identification of suitable end points, treatment of paediatric populations, lack of biomarkers for progression, and regulatory considerations.

  • Ongoing clinical trials for genetically defined neurodevelopmental disorders such as fragile X syndrome offer a valuable opportunity to learn about considerations for clinical development for ASD and related disorders.

Abstract

The rising rates of autism spectrum disorder (ASD) and the lack of effective medications to treat its core symptoms have led to an increased sense of urgency to identify therapies for this group of neurodevelopmental conditions. Developing drugs for ASD, however, has been challenging because of a limited understanding of its pathophysiology, difficulties in modelling the disease in vitro and in vivo, the heterogeneity of symptoms, and the dearth of prior experience in clinical development. In the past few years these challenges have been mitigated by considerable advances in our understanding of forms of ASD caused by single-gene alterations, such as fragile X syndrome and tuberous sclerosis. In these cases we have gained insights into the pathophysiological mechanisms underlying these conditions. In addition, they have aided in the development of animal models and compounds with the potential for disease modification in clinical development. Moreover, genetic studies are illuminating the molecular pathophysiology of ASD, and new tools such as induced pluripotent stem cells offer novel possibilities for drug screening and disease diagnostics. Finally, large-scale collaborations between academia and industry are starting to address some of the key barriers to developing drugs for ASD. Here, we propose a conceptual framework for drug discovery in ASD encompassing target identification, drug profiling and considerations for clinical trials in this novel area.

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Figure 1: Towards identification of the genetic basis of ASD.
Figure 2: Convergence of ASD risk factors on specific intracellular mechanisms.
Figure 3: Highly interconnected pathways offer opportunities for drug development.
Figure 4: Points of intervention for ASD.
Figure 5: Modes of action for the FDA-approved NMEs.
Figure 6: Use of iPSCs for ASD drug discovery.
Figure 7: Building clinical capabilities in neurodevelopmental disorders.

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Acknowledgements

The authors would like to thank M. Ebelin and J. Gottowick for their excellent support with the generation of the synaptic network for figure 3 and with information retrieval from drug databases for figure 5.

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  1. Aubin Michalon

    Present address: Present address: Neurimmune Holding, Wagistrasse 13, 8952 Schlieren, Switzerland.,

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  1. F. Hoffmann-La Roche, pRED, Pharma Research and Early Development, DTA Neuroscience, Grenzacherstrasse 124, Basel, 4070, Switzerland

    Anirvan Ghosh, Aubin Michalon, Lothar Lindemann, Paulo Fontoura & Luca Santarelli

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Glossary

Face validity

The extent to which an animal model's phenotype resembles human symptoms (e.g., an Alzheimer's disease model that progressively develops amyloid plaques and memory impairment).

Construct validity

The extent to which an animal model has the same aetiology and underlying mechanism as the human disorder (e.g., an Alzheimer's disease model generated by introducing a human presenilin mutation in the mouse)

RAS–MAPK–ERK pathway

RAS–mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase (ERK) pathway.

PI3K–AKT–mTOR pathway

Phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway.

CREB pathway

Cyclic AMP-response element-binding protein (CREB) pathway.

Long-term potentiation

(LTP). A persistent strengthening of synaptic transmission in response to strong, correlated input.

Long-term depression

(LTD). The converse of LTP; in LTD there is a long-lasting and activity-dependent decrease in synaptic efficacy.

Predictive validity

An animal model's ability to help identify drugs with potential therapeutic value in humans (e.g., antidepressant drugs reliably stimulate escape behaviours in the forced swim test, so the assay predicts antidepressant efficacy even if it does not measure depression).

Aberrant Behaviour Checklist

(ABC). A symptom checklist developed to assess problem behaviours of children and adults with severe intellectual disability, mapping behaviours into 5 subscales: irritability and agitation, lethargy and social withdrawal, stereotypical behaviour, hyperactivity, and inappropriate speech.

Social Responsiveness Scale

(SRS). A scale for quantitative measure of autism spectrum symptoms as they occur in natural social settings, specifically for social impairments such as social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. The SRS generates scores for five subscales: receptive, cognitive, expressive, and motivational aspects of social behaviour, as well as autistic preoccupations.

Vineland Adaptive Behaviour Scale

(VABS). A semi-structured interview instrument that measures adaptive behaviour in children and adults, covering major personal and social skills required for everyday living. It is commonly used to support the diagnosis of intellectual and developmental disabilities including autism. Five major domains (including specific subdomains) are assessed, including communication, daily living skills, socialization, motor skills and maladaptive behaviour.

Repeatable Battery for the Assessment of Neuropsychological Status

(RBANS). A brief neuropsychological battery that assesses cognitive decline or improvement, used as a neuropsychological screening battery for younger patients (down to 12 years). It tests five cognitive domains: immediate memory, visuospatial/constructional, language, attention and delayed memory.

Visual Analogue Scale

An instrument to assess subjective characteristics or attitudes that cannot be directly measured, in which respondents specify their level of agreement to a statement by indicating a position along a continuous line between two end points.

Clinical Global Impression (CGI) scale

A commonly used summary measure of a patients' global functioning. The CGI Severity is a seven-point categorical scale (from normal to extremely ill) that rates the severity of the disease at the time of assessment in comparison with past experience of patients with the same diagnosis. The CGI Improvement is a seven-point categorical scale (from very much improved to very much worse) that measures change in patient status from baseline in response to an intervention.

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Ghosh, A., Michalon, A., Lindemann, L. et al. Drug discovery for autism spectrum disorder: challenges and opportunities. Nat Rev Drug Discov 12, 777–790 (2013). https://doi.org/10.1038/nrd4102

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