Pharmacological Treatments for Autism Spectrum Disorder: Will Emerging Approaches Yield New Treatments?

Advances in modern genetics are rapidly changing the way we approach autism spectrum disorder (ASD) and other complex brain disorders. For example, massive sequencing efforts have identified over 50 ‘high confidence’ genes that possess intrinsic diagnostic and predictive value for ASD (De Rubeis et al, 2014; Iossifov et al, 2014). A post hoc analysis reveals that these genes encode protein products that are primarily localized to post-synaptic boutons and are involved in synthesis of synaptic proteins. Preclinical studies have begun to stratify syndromic forms of autism into groups defined by varying degrees of excitatory/inhibitory imbalance. Importantly, the phenotypic overlap among these disorders has provided optimism that viable therapeutics might emerge that show efficacy in both monogenetic and idiopathic ASD populations due to similarly disrupted signaling pathways.

Perhaps the most well studied potential therapeutic mechanism is that of metabotropic glutamate receptor 5 (mGlu₅) antagonism in fragile X syndrome (FXS), where genetic and pharmacological strategies of reducing mGlu₅-dependent protein synthesis have shown robust preclinical efficacy. However, the failure of two phase 2 clinical trials has caused many to question whether the target is viable (Jacquemont et al, 2014). An alternative approach is use of the GABA_B receptor agonist arbaclofen, which normalizes excessive protein synthesis and excitatory/inhibitory imbalance in FXS model mice. While a phase 2b clinical trial failed to achieve its primary endpoint of treating irritability, post hoc analysis with the Aberrant Behavior Checklist -Social Avoidance scale, a recently validated scale for the assessment of FXS, showed a treatment effect in the full study population. A post hoc subgroup of 27 subjects with more severe social impairment also showed improvements on the Vineland II socialization raw scores and on the Aberrant Behavior Checklist-Social Avoidance scale (Jacquemont et al, 2014).

Another ASD treatment strategy that is gathering momentum is the targeting of pleiotropic growth factors. In the case of Rett syndrome, small molecules mimicking the effects of brain derived neurotrophic factor or insulin-like growth factor 1 (IGF1) have efficacy in respiratory, cognitive and survival measures in preclinical studies (Castro et al, 2014; Kron et al, 2014). In fact, a recent trial concluded that recombinant human IGF1 improved respiratory and behavioral parameters in Rett syndrome patients, and patients are currently being recruited for phase 2b trials (Khwaja et al, 2014). Likewise, the IGF1 synthetic peptide, NNZ-2566, normalized spine density, hyperactivity and synaptic protein synthesis in a mouse model of FXS, and patients are currently being enrolled for phase 1 clinical trials (Deacon et al, 2015).

One common thread among these next generation ASD treatment strategies is that they normalize excitatory/inhibitory balance, in part, through the modulation of protein synthesis-dependent synaptic plasticity. These novel targets represent new access points to a pathway of genes disrupted in ASD patients, which may provide greater translational value than mGlu₅ antagonism. In addition, the recent failure of mGlu₅ modulators in FXS clinical trials does not invalidate the target, but rather highlights a need for a more complete understanding of the temporal, spatial and mechanistic subtleties underlying the inability of preclinical studies to translate to clinical populations, and the need to carefully consider patient stratification and appropriate outcome measures. Although it is too early to predict the ultimate impact of these advances on treatment of ASD, a renewed emphasis on these finer points of therapeutic design, coupled with the emergence of exciting new targets, represents important progress toward effective ASD treatments.

FUNDING AND DISCLOSURE

P Jeffrey Conn has been funded by NIH, Johnson & Johnson, AstraZeneca, Bristol-Myers Squibb, Michael J Fox Foundation, and Seaside Therapeutics. Over the past 3 years he has consulted for Pfizer, Cambridge, and has served on the Scientific Advisory Boards of Seaside Therapeutics, Michael J Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development Johns Hopkins University, Clinical Mechanism (POCM) and Proof of Concept (POC) Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. Rocco G Gogliotti declares no conflict of interest.