Download Developing new pharmacotherapies for autism C. Ecker , W. Spooren & D. Murphy

Review Article
doi: 10.1111/joim.12113
Developing new pharmacotherapies for autism
C. Ecker1, W. Spooren2 & D. Murphy1
From the 1Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, London, UK, and 2F. Hoffmann-La Roche Ltd,
Basel, Switzerland
Abstract. Ecker C, Spooren W, Murphy D (Institute of
Psychiatry, London, UK; F. Hoffmann-La Roche
Ltd,
Basel,
Switzerland).
Developing
new
pharmacotherapies for autism. (Review). J Intern
Med 2013; 274: 308–320.
Developing new pharmacotherapies for autism
spectrum disorder (ASD) is a challenge. ASD has
a complex genetic architecture, several neurobiological phenotypes and multiple symptom
domains. However, new opportunities are emerging
that could lead to the development of ‘targeted’ and
individualized
pharmacological
interventions.
Here, first we review these important new insights
into the aetiology and neurobiology of ASD with
particular focus on (i) genetic variants mediating
synaptic structure and functioning and (ii) differences in brain anatomy, chemistry and connectivity in this condition. The characterization of the
genotypic and phenotypic differences underlying
ASD might in the future be invaluable for stratifying the large range of different individuals on
the autism spectrum into genetically and/or
Introduction
Autism spectrum disorder (ASD) is a life-long
neurodevelopmental condition for which no cure
yet exists. Discovering novel treatments for ASD
remains a challenge; its aetiology and pathology
are largely unknown, the condition shows wide
clinical and phenotypic diversity, and case identification is solely based on symptomatology. Hence,
large-scale clinical trials are typically based on
samples of biologically and clinically heterogeneous individuals, and potential treatment effects
often remain undetected.
Yet, there is an increasing need for effective treatment development. It is currently estimated that
1% of all children have ASD [1], and the condition
is more common than paediatric cancer, diabetes
and AIDS combined. Furthermore, the high prevalence rate of ASD is growing (by approximately
10–17% annually), and consequently so is the
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biologically homogeneous subgroups that might
respond to similar targeted interventions. Secondly, we propose a strategic framework for the
development of targeted pharmacotherapies for
ASD, which comprises several different stages in
which research findings are translated into clinical
applications. The establishment of animal models
and cellular assays is important for developing and
testing new pharmacological targets before initiating large-scale clinical trials. Finally, we present
the European Autism Interventions – A Multicentre
Study for Developing New Medications (EU-AIMS)
Initiative, which was set up in the context of the
EU Innovative Medicines Initiative as the first
European platform for integrated translational
research in ASD. The EU-AIMS Initiative consists
of academic and industrial partners working in
collaboration to deliver a more ‘personalized’
approach to diagnosing and treating ASD in the
future.
Keywords: autism, biomarkers, drug development,
personalized medicine, translational research.
disease burden on affected individuals, their families and carers, and society as a whole. However,
new opportunities are emerging that might help
in the development of novel treatments and biomarkers for the condition. More than ever, there is
thus a strong need to establish multidisciplinary, integrated platforms that could facilitate
translational research to develop ‘targeted’ pharmacotherapies and personalized interventions for
ASD.
Here, we review the findings of recent studies that
might provide new and tractable opportunities to
identify ASD biomarkers across a variety of scientific disciplines and that underpin the discovery of
new pharmacological targets. In addition, we present the first European platform, the European
Autism Interventions – A Multicentre Study for
Developing New Medications (EU-AIMS) initiative,
which was set up to facilitate evidence-based
target-drug discovery in ASD.
C. Ecker et al.
Review Article: Developing new pharmacotherapies for autism
Heterogeneity of ASD: a complex challenge for developing
biomarkers and treatments
Autism spectrum disorder is a group of conditions
in which heterogeneity, both causative and phenotypic, is emerging as a dominant characteristic
[2]. Although a number of candidate genes have
been proposed to underlie ‘the autisms’ [3], recent
genetic findings suggest that idiopathic autism
(i.e. in contrast to ASD with known aetiology as a
result of, for example, Fragile X and Rett syndromes) is not a single-gene disorder. Rather, it
seems that ASD susceptibility is mediated by a
pattern of small and individually rare genetic
variants, copy number variations (CNVs), which
give rise to the ‘broader autism phenotype’. Individuals with this phenotype demonstrate (i) various degrees of symptom severity, (ii) different
neurocognitive profiles, (iii) several associated comorbid conditions and (iv) potentially different
neurobiological features. It is thus perhaps not
surprising that the diagnosis of ASD is still solely
based on symptomatology assessed via behavioural observations and/or clinical interviews.
Whilst the behavioural diagnosis of ASD has clear
advantages in the clinical setting, the aetiological
and phenotypic heterogeneity of ASD is less beneficial in the search for biomarkers and in the
development of treatments for the condition. For
example, most clinical trials conducted in this
field to date have shown small to moderate effect
sizes [4]. This might indicate a lack of suitable
pharmacotherapies for individuals with ASD. On
the other hand, it remains unclear whether such
small effect sizes in large-scale clinical trials might
also be due to the high degree of clinical/phenotypic heterogeneity within the ASD population
(e.g. strong effects within biologically homogeneous subgroups might be masked by small
effects across all individuals with ASD). Thus, it
is unlikely that ASD is treatable using a ‘one-sizefits-all’ approach. There is a strong need for
developing targeted treatments and interventions
that will be effective in some but not in all
individuals with ASD and lead to large effects
within particular autistic subgroups (Fig. 1). The
stratification of patients into more homogeneous
subgroups will therefore be crucial not only for the
development of biomarkers and treatments, but
also for the design of large-scale clinical trials.
Current evidence suggests that a potential patient
stratification could be based on the autism genotype and/or on its neurobiological phenotype.
Genotypic stratification of individuals with ASD
Autism spectrum disorder is known to be one of the
most heritable psychiatric conditions, with an
estimated heritability of 80% [5]. Despite the high
heritability, however, the number of ‘common’
genetic variants (i.e. genetic variants common to
all individuals with ASD) is surprisingly small, and
many of the reported common variants for ASD
lack replication. The lack of significant linkage or
genome-wide association (GWA) peaks may partially be due to methodological issues; for example,
the number of genetic loci investigated by GWA
studies often exceeds a few hundred thousand(s),
and statistically stringent thresholds – corrected
for multiple comparisons – are hence required to
detect reliable effects. On the other hand, these
findings might also suggest that the effect size of
the contribution of common alleles to ASD could be
smaller than originally thought.
An increasing number of genetic studies are therefore investigating the importance of distinct and
individually rare genetic variants in the aetiology of
ASD. For example, it is now known that CNVs (i.e.
deletions and duplications in the DNA sequence)
occur in 5–10% of ASD cases and might either be
inherited or can occur de novo (i.e. are present in a
child but not in either parent) [2]. In addition,
individual CNVs often have large effect sizes,
thought to be sufficient to ‘cause’ ASD. As recently
proposed by Betancur et al., [6] these findings
therefore constitute a conceptual shift from a
common disease–common variant (CDCV) model
to a common disease–multiple rare variant (CDMV)
model, where ASD is caused by multiple strongeffect variants, each of which is found in only a few
people.
Although the complexity of a CDMV model far
exceeds that of a CDCV model in conceptual terms,
it also offers a unique opportunity to identify rare
variants and/or CNVs in individuals with symptoms of autism and to stratify patients based on
their particular genotype. Considering the complex
genetic architecture of the condition, it is unlikely
that these autism genotypes are genetically identical (in terms of ASD-related genes). However,
subgroups could be established by maximizing
the genotypic variability across patient groups and
by minimizing genotypic variability within groups.
These homogeneous autism genotypes might also
be more similar in terms of their neurobiological
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(a)
(b)
Fig. 1 (a) The low to medium effect size of the current ‘one-size-fits-all’ approach for treating ASD might be due to the large
genetic and phenotypic heterogeneity of the condition and the presence of different ASD subgroups. (b) Thus, a more
‘personalized’ approach to treatment might be more effective in the future. Individuals are stratified into genetically or
phenotypically homogeneous subgroups (i.e. based on biomarkers) that might respond well to a particular type of treatment
(adapted from http://www.bayerpharma.com/).
phenotype and hence might respond to the same or
similar treatment(s).
Whilst the specific link between genotype and
neurobiological phenotype remains relatively unexplored in ASD, increasing evidence suggests that
the genotypic diversity underlying the condition
might indeed result in similar phenotypes, which
are characterized by similar ‘core’ deficits (i.e.
common to all individuals with ASD). For example,
it has recently been demonstrated that the multiple
rare de novo variants underlying ASD are closely
linked at the functional level and can be grouped
together to form clusters or networks of genes
based on their common functional involvement.
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Journal of Internal Medicine, 2013, 274; 308–320
Most importantly, however, many of the genes
forming these networks are primarily related to
synapse development, axon targeting and neuron
motility [7, 8]. Thus, perturbed synaptogenesis has
become a common underlying theme amongst the
numerous genetic variants associated with ASD at
the functional level.
Synaptic CNV in ASD: a potential target for treatment
The notion that synaptogenesis might represent a
common aetiological pathway for symptoms and
traits of autism also implies that ASD might be
treatable with drugs that specifically target synaptic molecules. For instance, many of the rare CNVs
C. Ecker et al.
Review Article: Developing new pharmacotherapies for autism
associated with ASD play a major role in synaptic
cell-adhesion molecule (CAM) pathways (2,6).
CAMs (reviewed in [9]) are a group of molecules
that are involved in the formation and maintenance
of synaptic contacts and include molecules responsible for (i) initiating contact between pre- and
postsynaptic cells, (ii) maintaining synaptic adhesion and (iii) providing ‘anchors’ for scaffolding
proteins that assemble signalling molecules,
neurotransmitter receptors and proteins in the
cytoskeleton. During neurodevelopment, CAMs
also provide a path for the so-called growth cone
at the tip of the developing axon and hence support
neurodevelopment even prior to synapse formation/initiation [10]. Thus, the presence of ASDlinked variations in genes and/or CNVs encoding
for CAMs suggests that the development and
plasticity of synaptic contacts might be atypical in
ASD and affect the way the brain is connected.
Furthermore, perturbed CAM pathway(s) might
affect not only synaptic structure and morphology,
but also function.
The best-established synaptic CNVs associated
with ASD are found in genes encoding the neuroligins, neurexins and SHANK3. Neuroligins are a
family of CAMs that are located postsynaptically
[11] and that are involved in the formation and
consolidation of both inhibitory and excitatory
synaptic contacts, depending on the specific subtypes (reviewed in [9]). Once the developing axon
reaches its target, neuroligins form a trans-synaptic contact with presynaptic neurexins, which is
believed to initiate synaptogenesis. Furthermore,
neuroligins and neurexins contain a postsynaptic
density (PSD) binding domain that mediates interactions with synaptic scaffolding proteins and
helps to anchor transmembrane proteins to the
cytoskeleton. Thus, both neuroligins and neurexins also play an important role in determining the
specificity and differentiation of synaptic contacts
[9]. For example, the neuroligin 1 subtype has been
found to primarily promote the formation of excitatory synapses, whereas neuroligin 2 is mainly
found on inhibitory synapses and preferentially
induces the formation of inhibitory contacts [12,
13]. It is noteworthy that the ASD-associated
neuroligin 3 [14, 15] seems to primarily promote
excitatory synaptogenesis. It has therefore also
been suggested that genetic variation in synaptic
CNVs associated with ASD might underlie a
potential disturbance in the excitation–inhibition
(E/I) balance (i.e. enhanced excitation) in ASD [16];
this will be discussed in further detail below.
Another gene associated with ASD that might
contribute to the E/I balance is SHANK3, which
encodes for a synaptic scaffolding protein that is
primarily located in the PSD [17]. The PSD is a
protein-dense region located immediately behind
the postsynaptic membrane, which primarily functions as a postsynaptic ‘organizing structure’ as it
assembles receptors, adhesion molecules and
signalling molecules that are required for synaptogenesis and synaptic signalling [18]. SHANK3
proteins interact with neuroligins to a considerable
degree and are hence also essential for synapse
formation and dendritic spine maturation. For
example, it has recently been demonstrated in
humans that mutations in SHANK3 strongly affect
the development and morphology of dendritic
spines (i.e. overexpression of wild-type SHANK3
significantly increased the number of spines compared with controls) and also reduce synaptic
transmission in mature neurons [17]. Variations
in SHANK3 primarily affect glutamatergic synapses
and might hence also contribute to an E/I imbalance in ASD.
Taken together, these genetic studies highlight the
important role of synaptic CNVs in the aetiology of
ASD and emphasize that the various CNVs associated with ASD might be classified based on their
common functional involvement in the development of brain connectivity (microscopic as well as
macroscopic) and mechanisms of neurotransmission. The identification of such common genetic
and neurobiological themes constitutes a crucial
step in the discovery of ‘mechanism-based’ therapeutics in ASD, offering a starting point for the
discovery of new pharmacological targets. Furthermore, these might be tested in genetic animal
models and/or cellular assays prior to large-scale
clinical trials. Given the emerging importance of
synaptic genes in ASD, an increasing number of
models are being developed to specifically target
synaptic and/or spine pathology.
Nongenetic risk factors for ASD
Despite all the evidence indicating a predominantly
genetic aetiology of ASD, more recent studies
suggest that the genetic origin and/or heritability
of ASD might not be as strong as originally thought
[19] and that nongenetic risk factors – in addition
to genetic variation – might significantly contribute
to ASD susceptibility [20]. Such nongenetic risk
factors include (i) epigenetic factors (see [21]), (ii)
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gulation/inflammation, oxidative stress and mitochondrial dysfunction and exposure to toxins (see
[22]) and (iii) nutritional and/or environmental
factors [23, 24] including the maternal–foetal
environment that might place the foetus at an
increased risk of ASD (i.e. the foetal programming
hypothesis; see [25]). In addition, it has been
shown that the risk of developing ASD is
significantly positively correlated with paternal
age, possibly caused by rare mutations arising in
the germ cell in the sperm of older fathers in
particular (reviewed in [26]). Such environmental
nongenetic factors are now being investigated by
large international collaborations, such as the
International Collaboration for Autism Registry
Epidemiology [27], so that specific factors can be
targeted by interventions to reduce the future risk
of developing ASD.
neuron connectivity and synaptic function, have a
reduced number of cortical GABAergic neurons
and abnormal neuronal migration [32]. A common
finding of studies using these animal models is the
important role of perturbed GABAergic and glutamatergic synaptic transmission in ASD, pointing
towards the possibility of developing new therapeutic approaches that specifically target mGluR5
signalling [33]. Furthermore, the available animal
models also highlight the importance of reversing
the effects of potential differences in spine morphology in ASD. Overall, there is increasing evidence to suggest that spine density is generally
increased in ASD, resulting in an increase in local
axonic connectivity (reviewed in [34, 35]). Thus, it
will be important to develop and test drugs that
could reduce the abnormally large number of
spines and potentially decrease the severity of
some behavioural deficits observed in ASD.
Animal models of and behavioural assays for ASD
The generation of predictive preclinical models that
are based on understanding of the genetic architecture of ASD is crucial for the discovery of
mechanism-based therapeutics in ASD (recently
reviewed in [28]). Such preclinical disease models,
for example using a variety of genetically engineered animal models, are invaluable not only for
drug discovery but also for isolating specific
aspects of the disease pathology, which can then
be compared with the human phenotype for validation and translation. In addition, animal models
allow the testing of drug feasibility and safety in an
iterative fashion, as well as the development of
behavioural assays that can be used to evaluate
drug efficacy at the behavioural level.
Several animal models are now available for ASD,
most of which highlight synaptic pathology/morphology and a potential E/I imbalance in ASD. For
example, mouse models of SHANK3 mutations
have been developed, which show significant alterations in synaptic protein levels and spine morphology as well as deficits in social interaction and
repetitive behaviour (see [29, 30]). Mouse models of
perturbed CAM pathways have also been developed
by the manipulation of genes encoding neurexins
and neuroligins. For instance, neuroligin-3 knockout mice demonstrate disrupted heterosynaptic
competition and perturbed metabotropic glutamate receptor (mGluR)–dependent synaptic plasticity [31]. Similarly, mice with a deletion in the
contactin-associated protein-like 2 gene (Cntnap2),
which encodes a neurexin protein involved in
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Phenotypic stratification of ASD
In parallel with genetic studies and animal models,
an increasing number of neurobiological investigations are also now directed towards the phenotypic
stratification of individuals with ASD, to resolve the
wide range of autism phenotypes into biologically
and phenotypically distinct subgroups. Whilst the
precise neurobiology of ASD remains elusive, it is
generally agreed that patients with the condition
differ from healthy individuals in several key neurobiological aspects including brain anatomy,
functioning, connectivity and neurochemistry,
which might significantly contribute to the development of biomarkers for ASD.
Brain anatomy and functioning in ASD
Structural neuroimaging studies suggest that the
brain of toddlers with ASD (2–4 years of age) is, on
average, larger than that of children without ASD
[36]. The overall increase in total brain volume
seems to disappear by the age of 5–6 years after
which no significant between-group differences are
typically observed. It has therefore been suggested
that the brain in ASD might undergo a period of
precocious accelerated growth during early postnatal life, which is then followed by an atypically
slow or arrested growth during childhood, so that
no global differences are generally observed in
adulthood [37]. The atypical neurodevelopmental
trajectory of brain maturation in ASD also seems to
be idiosyncratic for different lobes of the brain with
frontal and temporal lobes being more affected
C. Ecker et al.
Review Article: Developing new pharmacotherapies for autism
than parietal and occipital lobes [38]. Thus, the
normal temporal sequence of brain development
(i.e. from ‘back to front’ [39]) seems to be disturbed
in ASD, which will not only affect the development
of isolated brain regions but also the way the brain
is connected. ASD has therefore also been
described as a ‘neural systems’ condition, which
is characterized by subtle and spatially distributed
neuroanatomical differences in several large-scale
neurocognitive networks [40]. However, whilst the
notion of an abnormally enlarged brain and associated macrocephaly (i.e. head circumference
>97th percentile) might be one of the best-replicated findings with regard to ASD, it is certainly not
specific to this condition nor does it affect all
individuals on the autism spectrum; for example, it
is estimated that only 20% of children with ASD are
affected by macrocephaly (reviewed in [41]). Thus,
although macrocephaly might not be well suited as
a biomarker for ASD per se, general differences in
brain anatomy might still offer an opportunity for
patient stratification because of such variability
within the ASD group. Using novel pattern classification approaches, it is now possible to distinguish between and identify (i.e. predict ‘patients’ or
‘controls’) individuals with ASD and healthy control
subjects based on subtle and spatially distributed
patterns of multivariate biological data. To date,
most of these approaches have investigated the
predictive value of neuroimaging data, utilizing
information on brain structure [42, 43], functioning and connectivity (see [44, 45]). However, in the
future, it will be important to extend these
approaches to also incorporate information from
genetic studies as well as neurochemical markers
to build complex biomarker systems that could aid
diagnosis, enable patient stratification and predict
response to treatment(s).
Neurochemical markers for ASD
There is also evidence to suggest that differences in
brain chemistry and neurotransmission between
different individuals on the autism spectrum might
help to significantly reduce the large phenotype
variability between individuals with ASD. The
stratification of patients based on their individual
neurochemical make-up is of particular importance to the development of targeted treatment
strategies that maximize the individual’s response
to a particular pharmacotherapy. The three neurotransmitter systems that have attracted most
attention in ASD are the GABAergic, glutamatergic
and serotonergic systems.
GABA
Evidence for atypical GABAergic synaptic transmission in ASD comes from a variety of genetic
and neuroimaging studies, demonstrating inhibitory neurotransmission at several different levels
in ASD (reviewed in [46]). First, GABA plays a
crucial role during neurodevelopment where it acts
as a tropic factor to promote synaptogenesis to
influence different aspects of neuronal differentiation [47]. Thus, pathological perturbations in the
GABAergic system (e.g. via genetic variation/
expression) will affect the brain in a variety of
ways and will influence its structure and functioning beyond atypical synaptic transmission.
Secondly, in the mature brain, GABA is essential
for inhibitory neurotransmission, which might be
downregulated in ASD [48]. It is known that
glutamate decarboxylase (GAD)65 and GAD67 proteins – the two isoforms of the enzyme that
synthesize GABA in the presynaptic terminal –
are reduced in the brain of individuals with ASD,
which might result in reduced GABA synthesis
and thus reduced inhibition [49]. These differences might be of genetic or epigenetic origin as
several genetic variants highly associated with
ASD were amongst a number of genes encoding
for genes involved in GABA synthesis (e.g. GAD65
and GAD67 [50]) or GABA receptors (e.g. GABRB3
and GABRB5 [51]). In vivo neuroimaging studies
further demonstrate significantly reduced GABAA
receptor binding in ASD [52, 53], which might
exacerbate the existing deficits in GABA synthesis.
Although measuring GABAergic neurotransmission directly in the brain in vivo poses a methodological challenge, direct evidence has recently
been provide for reduced GABA concentration in
the brain in ASD. In a recent magnetic resonance
spectroscopy (MRS) study, a significantly reduced
GABA concentration in the frontal cortex was
observed [54]. Reduced GABAA receptor density
in both adults and children with ASD was also
shown in a single-photon emission computed
tomography study [55]. Finally, a recent pilot
study using positron emission tomography (PET)
demonstrated significantly reduced levels of
GABAA in adults with ASD [56]. The results of
most of these studies suggest that GABAergic
synaptic transmission might be reduced in
patients with ASD and that region-specific variations in GABA-related receptor expression and
transmitter concentration might contribute to
mediating the symptoms and traits of autism.
However, further studies are needed to confirm
these findings.
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Glutamate
Whilst GABAergic inhibitory neurotransmission
appears to be reduced in ASD, there is increasing
evidence to suggest that glutamatergic, and thus,
excitatory neurotransmission is enhanced (i.e. the
‘hyperglutamatergic hypothesis of autism’ [48]).
For example, individuals with ASD seem to have
higher-than-normal serum glutamate levels [57],
increased glutamate receptor mRNA [58],
increased mGluR expression [59] and increased
glutamate concentration as measured by MRS in
both the hippocampus and the auditory cortex [60,
61]. On the basis of the findings of studies investigating GABA and glumatate in ASD, it has also
been proposed that an important aspect of the
pathophysiology underlying ASD might be an E/I
imbalance in the brain (i.e. increased excitation
relative to the amount of inhibition) [16]. The
theory of imbalanced E/I has also been used to
explain some of the clinical symptoms associated
with ASD such as the increased incidence of
seizures and/or the hypersensitivity to visual/
auditory stimulation [16]. Taken together, these
findings will be important for the development of
drugs that could ‘normalize’ the E/I imbalance,
and a variety of pharmacological compounds have
recently been proposed to achieve this goal. On the
basis of the hypothesis that excessive metabotropic
glutamatergic signalling in ASD could cause some
of the core symptoms of the condition, the findings
of several studies suggest a potential beneficial
effect of mGluR5 antagonists, or arbaclofen, which
reduces glutamate-mediated receptor activation at
synapses (reviewed in [62]). These drugs provide
examples of an evidence-based approach to the
development of pharmacotherapies for ASD taking
into account both genotypic and phenotypic data
and thus allowing in vitro validation prior to clinical
trials.
Serotonin (5-HT)
There is also preliminary evidence implicating
abnormalities in the serotonergic system in ASD.
Unlike other neurotransmitters (e.g. GABA and
glutamate), the biosynthesis of 5-HT requires the
presence of a dietary source of the amino acid Ltryptophan (TRP), which can cross the blood–brain
barrier. TRP is hydroxylated through the actions of
the enzyme tryptophan hydroxylase to produce the
intermediate 5-hydroxytryptophan (5-HTP). The
resultant 5-HTP is then decarboxylated by the
aromatic L-amino acid decarboxylase to produce
serotonin. It has been suggested that a significant
proportion of individuals with ASD might have
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‘hyperserotonemia’ [63, 64]. For example, a significantly higher 5-HT concentration in whole blood
sample was observed in children with ASD as well
as their relatives (e.g. [65]). In vivo neuroimaging
studies show that individuals with ASD have
significant differences in serotonin synthesis compared with healthy control subjects, as well as a
reduction in serotonin receptor binding and in the
number of 5-HT transporters, particularly in brain
regions involved in social communication such as
the cingulate cortices [66–68]. Finally, significant
genetic association between ASD and genetic polymorphisms for serotonin synthesis, transporters
and receptors has been observed [69–71]. On the
basis of these findings, it has also been suggested
that individuals with ASD may benefit from drugs
that modulate the serotonergic system. Despite the
notion of hyperserotonemia in ASD, most studies
have so far focused on the effects of selective
serotonin reuptake inhibitors (SSRIs). The administration of SSRIs has, however, not been proven to
be effective in the treatment of all individuals with
ASD [4]. Nevertheless, it remains unclear whether
small effect sizes in large-scale clinical trials are
mainly due to the high degree of clinical/phenotypic heterogeneity within the ASD population. For
instance, Hranilovic et al. reported that hyperserotonemia might only be present in about 30% of
individuals with ASD [64]. It is therefore of important to develop tools that could identify those with
hyperserotonemia prior to examining the effectiveness of serotonergic pharmacotherapy to specifically tailor the type of modulation required.
Furthermore, other recent studies have also highlighted the potential beneficial effects of serotonin
reuptake enhancers on the severity of autismrelated symptoms and traits [72, 73]. In the future,
such studies examining the effects of both enhancers and inhibitors in a variety of ASD subgroups might prove invaluable in developing
personalized treatment strategies. Such basic clinical and pharmacological studies therefore play an
important and integral role in the translational
research cycle that will lead to the discovery and
evaluation of new treatments for ASD.
The translational cycle in the development of targeted treatments
for ASD
The translation of research findings into clinically
useful biomarkers and pharmacotherapies that are
based on understanding of the pathophysiology of
ASD is complex and lengthy. It involves multiple
stages of interdisciplinary research that are
C. Ecker et al.
Review Article: Developing new pharmacotherapies for autism
Fig. 2 Translational research cycle for the discovery of novel targeted pharmacotherapies for ASD. The cycle combines
phenotypic and genotypic research with animal and in vitro models that can be used for the informed and integrated
development of pharmacological targets. Work packages (WP) 1–4 are part of the European Autism Interventions – A
Multicentre Study for Developing new Medications (EU-AIMS) network, the first European platform for translational research
in ASD.
conducted predominantly in parallel, yet inform
each other. The stages of the translational research
‘cycle’ (Fig. 2) generally include the clinical and
behavioural characterization of the human phenotype of the condition, followed by the identification
of its genotype(s) [74]. In ASD, both genotypes and
phenotypes are likely to be multifaceted, which
introduces an additional level of complexity to the
cycle. The identification of ASD genotypes then
makes it possible to develop animal models and
cellular assays that mimic the pathology or certain
pathological features. For instance, animal models
now exist of perturbed synaptogenesis and imbalanced E/I. These models can be used to test
pharmacological compounds that target the specific aspect of pathology under controlled conditions. Such novel treatments might be designed to
reduce the abnormally high spine density in individuals with ASD and/or to normalize the E/I
balance. Following the successful exploration and
validation of these compound using animal models, their effectiveness can then be tested in
large-scale clinical trials in humans that will finally
determine the effectiveness and success of a particular treatment.
Because of its multidisciplinary character, translational research for the development of stratified
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Eli Lilly and Company Ltd.
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Pfizer Limited
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(Neurospin/CEA) France
aux Energies Alternatives
Commissariat a l’Energie Atomique et
University Ulm (Germany)
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development
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research development
Translational
WP 03
Birkbeck, University of London (UK)
Karolinska Institutet (Sweden)
Laboratory (Germany)
European Molecular Biology
x
x
x
x
Max-Planck-Gesellschaft (Germany)
x
x
x
development
Animal model
development
system
Institute Pasteur (France)
Basel (Switzerland)
Biozentrum, University of
(the Netherlands)
University Medical Centre Utrecht
Cambridge University (UK)
Centre (the Netherlands)
Nijmegen Medical
Radboud University of
Mannheim (Germany)
Mental Health,
Central Institute of
King’s College London (UK)
Academic partners
Consortium Partners
WP 02
WP 01 In vitro
Table 1 Consortium Partners of the EU-AIMS Initiative and their involvement in individual work packages (WP)
x
x
x
x
x
biological samples
of data and
Management
WP 05
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
management
Project
WP 06
C. Ecker et al.
Review Article: Developing new pharmacotherapies for autism
x
x
x
x
x
x
x
x
x
medicines is a logistic challenge, particularly for
ASD. It requires the orchestrated management of (i)
multiple collaborating research centres, which conduct basic research at various levels of magnification; (ii) multiple control instances that assure data
quality and compatibility of scientific findings
between sites; (iii) ethical approval and supervision
of clinical trials testing novel pharmacological
agents; and (iv) the clinical evaluation of outcome
measures and the distribution of pharmacotherapies in collaboration with industry. To date, however, there has been a lack of available platforms
that could be utilized for conducting translational
research in ASD. European efforts are therefore now
directed at developing the infrastructure required to
implement all stages of the translational research
cycle in ASD within the same consortium.
The EU-AIMS Initiative: a European model for translational
research in ASD
x
The EU-AIMS is a platform that was recently set up
in the context of the EU Innovative Medicines
Initiative (IMI) to facilitate translational research
in ASD [75]. The EU-AIMS consortium consists of
14 leading European academic centres in collaboration with ‘Autism Speaks’ (world-leading charity
for ASD), ‘Autism Europe’ (representing patients
and carers) and industrial partners (three mediumsized enterprises and six members of the ‘European Federation of Pharmaceutical Industries and
Associations’) (see Table 1). The aim of the network
is to deliver new tools and standards for evidencebased drug discovery and clinical trials in ASD by
integrating and translating research efforts at
various levels (e.g. clinical and preclinical). EUAIMS brings together five overlapping themes that
will underpin drug discovery in five different work
packages (WPs) representing the different stages of
the translational research cycle.
Autism Speaks (Charity)
GABO:mi (Germany)
(the Netherlands)
Noldus Information Technology
x
NeuroSearch (Denmark)
deCODE Genetics (Iceland)
Autism Speaks (UK Charity)
management
biological samples
x
development
research development
development
development
x
Vifor Pharma
Consortium Partners
of data and
Clinical research
Translational
Animal model
system
Project
Management
WP 04
WP 03
WP 02
WP 05
Table 1 (Continued )
Review Article: Developing new pharmacotherapies for autism
WP 01 In vitro
WP 06
C. Ecker et al.
The aim of WP1 is to develop cellular assays (e.g.
using induced pluripotent stem cells [76]) that can
be used to model the genetic deficits of ASD in vitro,
and subsequently facilitate the identification of
different cellular/molecular phenotypes of ASD
and to relate phenotypes to disease-specific genetic
variants. In addition, cellular assays allow the in
vitro development and testing of new drugs for ASD
that can then be translated into animal models and
humans.
WP2 is predominantly concerned with the development of animal models and behavioural assays
ª 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 308–320
317
C. Ecker et al.
Review Article: Developing new pharmacotherapies for autism
for ASD and will be informed by (and inform) WP1.
The existing rodent models can be used to represent different potential pathways for ASD as well as
for in vivo evaluation of treatment targets, such as
GABA and serotonin.
WP3 involves the validation of biomarkers that
facilitate the drug discovery process and that
might be used to aid diagnosis, stratify patients
and predict response to treatment. Biomarkers will be developed based on available data
characterizing the human intermediate phenotype
of ASD. Such phenotypic data will be based on
various
neuroimaging
measures
of
brain
anatomy, functioning and connectivity in ASD,
in addition to electrophysiological findings and
neurochemical measures acquired by PET and
MRS.
WP4 facilitates clinical research development by
creating an EU infrastructure of expert clinical
research sites to (i) coordinate and standardize
recruitment and data acquisition in several countries for large-scale clinical trials, (ii) provide expert
clinical advice to inform the complex process of
drug development and (iii) create a bioresource of
phenotypic data in a well-characterized sample of
individuals with ASD including both men and
women with various stages of neurodevelopment
and different autism phenotypes. Of note, an
additional aim of WP4 is to develop a new EU
‘high-risk’ infant sibling network to address the
important questions of early diagnosis and predictive value of biomarkers for ASD. The data acquired
across WPs will then be managed and made
available as a large-scale ‘bioresource’ for ASD in
WP5, which represents the efforts of a large-scale
integrated network of academic centres, industry,
charities and affected individuals with ASD on the
way to developing targeted drugs and treatments
for ASD.
Conclusions
Despite the high genetic and phenotypic diversity
of ASD, new opportunities are now emerging that
might lead to the development of novel pharmacotherapies for patients with ASD. The mechanism-based development of targeted treatments
requires extensive multidisciplinary research that
is currently being conducted as part of the EUAIMS Initiative, and globally. However, it is
unlikely that a single compound will be effective
in all individuals with ASD, and it is therefore
318
ª 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 308–320
important also to develop biomarkers that might
be used to stratify patients depending on their
genotype and/or neurobiological phenotype. These
novel approaches and collaborative efforts represent a significant step towards a more personalized approach to diagnosing and treating ASD in
the future, with the best possible likelihood of
success.
Acknowledgements
This work was supported by the Autism Imaging
Multicentre Study (AIMS) Consortium funded by
the Medical Research Council, UK (G0400061); the
EU-AIMS receiving support from the Innovative
Medicines Initiative Joint Undertaking under grant
agreement no. 115300, which includes financial
contributions from the EU Seventh Framework
Programme (FP7/2007-2013), from the EFPIA
companies in kind and from Autism Speaks
(http://www.eu-aims.eu); the Dr. Mortimer and
Theresa Sackler Foundation, the NIHR Biomedical
Research Centre for Mental Health at King’s College London, Institute of Psychiatry, and South
London and Maudsley NHS Foundation Trust.
Conflict of interest statement
W. Spooren is employed by F. Hoffmann-La Roche.
Neither of the other authors has any conflict of
interests or financial interests to declare.
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Correspondence: Christine Ecker, Department of Forensic and
Neurodevelopmental Sciences and Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, De Crespigny
Park, London, SE5 8 AF, UK.
(fax: +44 (0) 207 848 0281; e-mail: [email protected]).