Reviewing Autism: Can Biotech open up New Horizons?

While Autism Spectrum Disorders (ASD) affect approximately one in 68 children, this hasn’t provoked much enthusiasm among pharmaceutical companies to develop drugs.  However, recent advances in basic research Autism and novel gene-editing technologies may boost ASD drug development.

The reasons for low interest are a poor understanding of the biological mechanisms underlying Autism Spectrum Disorder, the multiple symptoms that make ASD difficult to diagnose and a shortage of animal models for the disease.

ASD is a general term for a wide spectrum of neurological disorders that share a general pattern of symptoms: repetitive behaviours, abnormal social interactions and impaired cognitive functions. These characteristics are frequently accompanied by epilepsy and intellectual disability, amongst others.

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Fig 1. Interaction of symptoms which often accompany ASD (Source: Autism Reading Room)

The severity of the symptoms arises from a combination of an individual’s genetic background and environmental factors. Many ASD disorders, such as the rare Fragile X syndrome, are passed on genetically, while others originate from novel genetic mutations that arise in only one family member.


The number of genes implicated in ASD ranges between 200 and 1000 and surprisingly, many of these are involved not only in brain function and development, but also metabolism and the development of bone and tissue.

For example, in addition to ASD symptoms, children with the rare ‘14q11.2 microdeletion syndrome’ have distinct facial abnormalities and poor gastro-intestinal function. This syndrome results from the deletion of at least two genes (CHD8 and SUPT16H). More genes may be lost from the chromosome, however, and the greater the number, the more severe the symptoms.

Scientists have been baffled by both the number of candidate genes and the diverse roles they play in the body, which makes it hard to identify underlying causes for ASD. This also makes it nearly impossible to design a drug, since it is unclear which specific gene or protein such a drug would need to hit.

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Fig 2. Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) provides unprecedented opportunities in generating human disease models. However, the main barrier to developing ASD candidates is the overwhelming number of genes involved in this neurodevelopmental disorder.

Indeed, it is generally known that drugs aimed at multiple targets have poor efficiency and will likely result in side-effects…and only 6 new drugs that target various symptoms of ASD are currently in clinical trials

A final hurdle is the fact that to be approved for use in humans, a drug must first be tested in comparable animal models; and so far only a few such models exist for ASD. This may change through the advent of the gene-editing technology CRISPR/Cas9, which can reduce the time needed to make ASD animal models.

Until these new animal models (such as mice) become available, ASD research and development is roaming in the dark.

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Several clinical trials evaluating compounds for ASD have also failed in recent years…

The development of these trials was sponsored by EU pharma giants Roche and Novartis. A third partner, Seaside therapeutics (US) completely dissolved following the failure to demonstrate significant effect of the drug compared to the placebo control, which might have been due to the advanced age of the patients in the trial.

Scientists anticipate that the same drugs might act more efficiently in children, due to the higher plasticity of their developing brains.

Seaside Therapeutics had a candidate (STX209) in phase III trials for Social Withdrawal in children with Fragile X Syndrome (the leading cause of Autism) to correct the altered protein synthesis at synapses. This target endpoint with STX209 was also being trialled in phase II trials for ASD up to the ages of 21, when the trials were withdrawn.

The supposed reasons for the withdrawal include insufficient funds, the FDA’s ‘limiting single endpoint’ regulations and the relatively advanced age of the patients in the trial.

So despite advances that suggest promising avenues for research, pharmaceutical companies therefore tend to shy away from ASD drug development. Indeed, to date only 20 clinical trials on ASD drugs are running. 

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The loss of FMRP leaads to excess fragile X protein synthesis. STX209 (arbaclofen) was shown to restore this balance in mice to normal levels by activating GABAB receptors, thought to work by affecting glutamate release (either directly, as shown, or by dampening electrical activity in excitatory neurons) (Source: Business Wire / Seaside Therapeutics)

So who in Europe is working on ASD Now?

The Swiss giant, Roche is leading the charge, having developed a compound called RG7314 that acts as an antagonist of the Vasopressin-1 receptor; phase II trials should be completed by 2017.

In addition, Roche is part of the largest multi-center project addressing ASD. The EU-AIMS project has secured a grant of €35.2M – the largest single grant for autism in the world – and ever seen in the mental health sector.

It functions as an international consortium of 20 European companies led by Roche and King’s College London‘s (Institute of Psychiatry) which has launched one of the largest ever research academic-industry collaboration projects to work alongside patients and their families (through the charity Autism Speaks).

Others involved include elite research centres from the UK ‘Golden Triangle’ (such as the European Bioinformatics Institute and the University of Cambridge), the Icelandic leader in genomics (deCODE), the Karolinska Institutet in Sweden and many others.

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Generally though the diversity of Autism-related genes and the chronic nature of the disease present numerous challenges to the development of treatments. 

That may change through the rise of powerful new technologies and a greater understanding of the mechanisms that cause ASD. So there is a lot still to hope for!

Companies willing to tackle these issues will be able to draw on new technologies and benefit from the increasing public awareness of this class of disorders, which seriously disrupt the lives of affected children and their families.


Figure 1: Huguet et al. (2013) The Genetic Landscapes of Autism Spectrum Disorders, Annual Reviews: Genomics & Human Genetics.

Figure 2: Kim & Jung et al. (2012) Cellular reprogramming: a novel tool for investigating autism spectrum disorders, Trends in Molecular Biology, doi: 10.1016/j.molmed.2012.06.002

Feature Image Credit: Beautiful Brains © Sergey Nivens (BigStock ID81093296)

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