Clinical Phenotype of Autism Spectrum Disorder: Development and Delivery of Therapeutic Biomolecules to the CNS

Dear Colleagues,

Medication interventions for autism spectrum disorder(s) (ASD), highly prevalent neurodevelopmental disorders with high heritability that present more commonly in boys than girls, target “challenging” behaviors, as opposed to their underlying mechanisms of pathogenesis and etiologies. Moreover, although molecular genetic strategies are identifying genetic abnormalities associated with ASDs, such as sequence variants (e.g., missense variants), protein-truncating variants (PTVs), and copy number variants (CNVs), the latter often resulting from non-homologous recombination mechanisms, expressed phenotypes can be variable with “imperfect” genotype–phenotype relationships. In retrospect, identifying predictive associations between genotypes and clinical phenotypes may have been unrealistic because clinical presentations reflect poorly appreciated interactions between genetic background; in utero environment; maternal stress, nutritional status, and inflammation during pregnancy; as well as the early rearing environment of the infant. Moreover, relationships between density of CNVs, which are microdeletions and microduplications that affect “gene dosage” and transcriptional efficiency, have raised interesting questions about shared genetic architecture between disorders that were previously thought to be separate and distinct from each other, such as ASD, schizophrenia, idiopathic seizure disorders, and intellectual disability. Risk alleles, proteins, and pathways associated with ASD affect synaptic development, architecture (e.g., neurexins, neuroligins, and Shank proteins) and function (e.g., GABA_A and NMDA receptor subunits); regulation of transcription (e.g., chromodomain-helicase-DNA-binding protein 8 [CHD8]) and translation (e.g., fragile X mental retardation protein 1 [FRP1]); innate and adaptive immunity; and neuronal excitability (e.g., sodium voltage-gated channel alpha subunit 2 [SCN2A]), among other complex and interdependent effects. Development of targeted pharmacotherapeutic strategies for ASD must take into account developmentally-regulated genetic expression and effects on cell function of the targeted genes, proteins, and pathways. Thus, studies may explore the effects of transfecting pathogenic genetic variants in heterologous expression systems (e.g., HEK293 cells) on such diverse outcomes as ion flux across membranes, gene expression, and changes in sensitivity to damage by a variety of metabolic and oxidative stressors. Further, studies seeking “correlations” of behavioral phenotypes associated with genetic variants of transgenic mice bred on a variety of genetic backgrounds with clinical phenotypes may be informative. Transgenic mice tested in standardized behavioral paradigms may prove useful to characterize deficits of social preference, interaction and memory (e.g., the 3-chamber sociability apparatus and recordings of ultrasonic vocalizations) and spatial learning and memory (e.g., the Morris water maze task), among other behavioral paradigms, which may lead to “predictive” preclinical models of ASD. These validated transgenic mouse models (i.e., those showing reproducible deficits of social preference/interaction and cognition) will be employed to screen novel pharmacological strategies, which will include repurposed medications and novel chemical entities (NCEs). Additionally, there is active interest in developing and delivering medicines to the CNS that possess selectivity for specific molecular targets and cell populations and, thereby, avoidance of off-target adverse and toxic effects; interest includes the development of delivery systems for non-polar compounds and peptides. A variety of future medicines may selectively target allosteric modulatory sites and intracellular signal transduction pathways, as opposed to orthosteric binding sites. As noted, these medicines may reach their specific targets with novel CNS delivery systems designed to overcome limitations of blood-brain barrier penetrability and proteolytic digestion. The Guest Editors view this Special Issue as a productive first step in familiarizing biomolecular engineers, medicinal chemists, biochemical pharmacologists, and preclinical psychopharmacologists with the clinical dimensions of ASD. This Special Issue of Biomolecules is a platform for investigators in these various disciplines to recognize promising translational clinical implications and applications of their work and suggest areas for collaboration. The enormity of the problem (recently estimated prevalence of ASD is as high as 1 in 59 children) and impact of ASD on adaptive functioning in those affected, including underappreciated social and economic impacts on families, make rapid progress in this area a moral imperative.

Dr. Stephen I. Deutsch
Dr. Jessica Burket
Guest Editors

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• autism spectrum disorder
• phenotype
• genotype
• pharmacology