scholarly journals Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1746
Author(s):  
Verica Vasic ◽  
Mattson S. O. Jones ◽  
Denise Haslinger ◽  
Lisa S. Knaus ◽  
Michael J. Schmeisser ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Clinical Trials ◽  
Human Cell ◽  
Neuronal Development ◽  
Cell Model ◽  
Neuropsychiatric Symptoms ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Model Systems ◽  
Ras Signaling

Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

New Strategies for Clinical Trials in Autism Spectrum Disorder

2020 ◽  
Vol 15 ◽  
Author(s):  
Rini Pauly ◽  
Catherine A. Ziats ◽  
Ludovico Abenavoli ◽  
Charles E. Schwartz ◽  
Luigi Boccuto
Keyword(s):  
Autism Spectrum Disorder ◽  
Clinical Trials ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genetic Profiling ◽  
Omics Technologies ◽  
Molecular Abnormalities ◽  
Sequencing Technologies ◽  
Linear Relationships ◽  
Personalized Approach

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that poses several challenges in terms of clinical diagnosis and investigation of molecular etiology. The lack of knowledge on the pathogenic mechanisms underlying ASD has hampered the clinical trials that so far have tried to target ASD behavioral symptoms. In order to improve our understanding of the molecular abnormalities associated with ASD, a deeper and more extensive genetic profiling of targeted individuals with ASD was needed. Methods: The recent availability of new and more powerful sequencing technologies (third-generation sequencing) has allowed to develop novel strategies for characterization of comprehensive genetic profiles of individuals with ASD. In particular, this review will describe integrated approaches based on the combination of various omics technologies that will lead to a better stratification of targeted cohorts for the design of clinical trials in ASD. Results: In order to analyze the big data collected by assays such as whole genome, epigenome, transcriptome, and proteome, it is critical to develop an efficient computational infrastructure. Machine learning models are instrumental to identify non-linear relationships between the omics technologies and therefore establish a functional informative network among the different data sources. Conclusion: The potential advantage provided by these new integrated omics-based strategies is to better characterize the genetic background of ASD cohorts, identify novel molecular targets for drug development, and ultimately offer a more personalized approach in the design of clinical trials for ASD.

scholarly journals Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature

2019 ◽  
Author(s):  
Patricia Kabitzke ◽  
Diana Morales ◽  
Dansha He ◽  
Kimberly Cox ◽  
Jane Sutphen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Model Systems ◽  
Activity Levels ◽  
Phenotypic Differences ◽  
Genetic Mouse Model ◽  
Unitary Concept

3.AbstractBackgroundPhenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD.MethodsTo assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to look for commonalities and differences.ResultsResults in the current study were very similar to our previously published results. The informatics signatures of the two model systems chosen for the replication showed that they were most distinguished by activity levels. Although the two model systems were opposite in this regard, those aspects of their social behavior not confounded by activity (vocalizations) were similar.ConclusionsOur results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle differences in testing conditions, housing enrichment, or background strains and not so much on the variability of the behavioral phenotypes. The overall informatics analysis suggests two main classes of model systems that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.

scholarly journals Anti-NMDA Receptor Encephalitis in a Patient with a History of Autism Spectrum Disorder

2020 ◽  
Vol 10 (3) ◽  
pp. 231-235
Author(s):  
Xavier Diao ◽  
Milana Mor
Keyword(s):  
Autism Spectrum Disorder ◽  
Nmda Receptor ◽  
Neuropsychiatric Symptoms ◽  
Antipsychotic Agents ◽  
Altered Mental Status ◽  
Autism Spectrum ◽  
Acute Onset ◽  
Spectrum Disorder ◽  
Nmda Receptor Encephalitis ◽  
History Of

Background: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune syndrome characterized by a well-described constellation of neuropsychiatric symptoms. Its exact pathophysiology is poorly understood, but it is thought to be mediated by autoantibodies against NMDA (N-methyl-D-aspartate)-type glutamate receptors in the central nervous system. There is ongoing literature to suggest that patients with autism spectrum disorder (ASD) have evidence of neuroinflammation—or by definition, encephalitis. Objective: To investigate the link between autism spectrum disorder and autoimmune encephalitides. Methods: We present a case of anti-NMDA receptor encephalitis in a patient with autism spectrum disorder. “OP” is a 16-year-old male with a history of attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) who presented with a 3-day history of acute-onset altered mental status, electroencephalogram (EEG)-corroborated seizures, and slurred speech. Laboratory studies were significant for serum- and cerebrospinal fluid (CSF)-positive NMDA antibodies. The child psychiatry consult-liaison service was consulted for significant agitation and behavioral dyscontrol. We recommended 1:1 observation for safety, as well as antipsychotic agents titrated to clinical effect. The patient had a protracted hospital course, but was eventually discharged to an acute rehabilitation facility for continued stabilization and therapy. Conclusion: It remains to be seen if the relation between encephalitis and ASD is uni- or bidirectional, that is: whether children with ASD have a genetic diathesis to developing encephalitides (such as those mediated by the NMDAR), or conversely, if deranged or inflamed neuroreceptor processes are implicated in the development of ASD.

Novel Therapeutics in Childhood Onset Psychiatric Disorders

2013 ◽  
pp. 1061-1064
Author(s):  
Dorothy E. Grice ◽  
Alexander Kolevzon ◽  
Walter E. Kaufmann ◽  
Joseph D. Buxbaum
Keyword(s):  
Autism Spectrum Disorder ◽  
Clinical Trials ◽  
Down Syndrome ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Model Systems ◽  
Childhood Onset ◽  
Preclinical Evaluation ◽  
Novel Therapeutics

Neurodevelopmental disorders are frequently the result of genetic and genomic abnormalities associated with high risk for disease. Creating analogous mutations in cell and animal models permits the assessment of underlying neurobiological mechanisms, generates clues about useful therapeutic targets, and provides systems for preclinical evaluation of novel therapeutics. This chapter briefly summarizes several clinical trials in neurodevelopmental disorders, all based on neurobiological findings in model systems, including trials in Down syndrome (DS) and several monogenic forms of intellectual disability (ID) and/or autism spectrum disorder (ASD).

scholarly journals Downregulation of an Evolutionary Young miR-1290 in an iPSC-Derived Neural Stem Cell Model of Autism Spectrum Disorder

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Dalia Moore ◽  
Brittney M. Meays ◽  
Lepakshe S. V. Madduri ◽  
Farah Shahjin ◽  
Subhash Chand ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Stem Cell ◽  
Neuronal Differentiation ◽  
Neural Stem Cell ◽  
Cell Model ◽  
Critical Role ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Induced Pluripotent

The identification of several evolutionary young miRNAs, which arose in primates, raised several possibilities for the role of such miRNAs in human-specific disease processes. We previously have identified an evolutionary young miRNA, miR-1290, to be essential in neural stem cell proliferation and neuronal differentiation. Here, we show that miR-1290 is significantly downregulated during neuronal differentiation in reprogrammed induced pluripotent stem cell- (iPSC-) derived neurons obtained from idiopathic autism spectrum disorder (ASD) patients. Further, we identified that miR-1290 is actively released into extracellular vesicles. Supplementing ASD patient-derived neural stem cells (NSCs) with conditioned media from differentiated control-NSCs spiked with “artificial EVs” containing synthetic miR-1290 oligonucleotides significantly rescued differentiation deficits in ASD cell lines. Based on our earlier published study and the observations from the data presented here, we conclude that miR-1290 regulation could play a critical role during neuronal differentiation in early brain development.

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