Do animal models hold value in Autism spectrum disorder (ASD) drug discovery?

Chadman, Kathryn K.; Fernandes, Stephanie; DiLiberto, Elizabeth; Feingold, Robert M

doi:10.1080/17460441.2019.1621285

Cited by 17 publications

(16 citation statements)

References 70 publications

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“…In order to understand the neural and behavioral consequences of the gene mutations thought to underlie ASD and to test novel therapeutics, many genetically modified mouse models have been developed 40‐44 . To date (May 2020) at least 20 ASD mouse models are available from the SFARI 45 program at JAX labs [https://www.sfari.org/resource/mouse-models/].…”

Section: Introductionmentioning

confidence: 99%

“…Since ASD is a behaviorally defined disorder, it is essential to link the genotype of the mouse model with its neuro‐behavioral phenotype and ensure that it is a reliable and valid model of ASD 28,46‐50 . Because autism involves a wide spectrum of behavioral phenotypes, a single mouse model representing all of the features of ASD is unlikely, thus different mouse models reflect different aspects of ASD 42‐44,51‐55 …”

Section: Introductionmentioning

confidence: 99%

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The effect of background strain on the behavioral phenotypes of the MDGA2^+/− mouse model of autism spectrum disorder

Fertan

Wong

Purdon

et al. 2020

Genes Brain and Behavior

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The membrane‐associated mucin (MAM) domain containing glycosylphosphatidylinositol anchor 2 protein single knock‐out mice (MDGA2+/−) are models of ASD. We examined the behavioral phenotypes of male and female MDGA2+/− and wildtype mice on C57BL6/NJ and C57BL6/N backgrounds at 2 months of age and measured MDGA2, neuroligin 1 and neuroligin 2 levels at 7 months. Mice on the C57BL6/NJ background performed better than those on the C57BL6/N background in visual ability and in learning and memory performance in the Morris water maze and differed in measures of motor behavior and anxiety. Mice with the MDGA2+/− genotype differed from WT mice in motor, social and repetitive behavior and anxiety, but most of these effects involved interactions between MDGA2+/− genotype and background strain. The background strain also influenced MDGA2 levels and NLGN2 association in MDGA2+/− mice. Our findings emphasize the importance of the background strain used in studies of genetically modified mice.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effect of background strain on the behavioral phenotypes of the MDGA2^+/− mouse model of autism spectrum disorder

Fertan

Wong

Purdon

et al. 2020

Genes Brain and Behavior

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“…For over two decades, evidence of the beneficial effects of SF has accumulated, extending from in vitro studies, to animal models, to a variety of clinical studies 6,[12][13][14][15] . Importantly, there are currently no drugs approved to treat the core symptoms of ASD, nor are there any studies using SF in genetic mouse models of ASD 16 . The cytoprotective potential of SF extending even to maternal dietary supplementation to prevent perinatal brain injury has been considered 17 .…”

mentioning

confidence: 99%

Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder

Liu

Zimmerman

Singh

et al. 2020

Sci Rep

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Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders with no drugs treating the core symptoms and no validated biomarkers for clinical use. The multi-functional phytochemical sulforaphane affects many of the biochemical abnormalities associated with ASD. We investigated potential molecular markers from three ASD-associated physiological pathways that can be affected by sulforaphane: redox metabolism/oxidative stress; heat shock response; and immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with ASD. We first analyzed the mRNA levels of selected molecular markers in response to sulforaphane ex vivo treatment in PBMCs from healthy donors by real-time quantitative PCR. All of the tested markers showed quantifiability, accuracy and reproducibility. We then compared the expression levels of those markers in PBMCs taken from ASD patients in response to orally-delivered sulforaphane. The mRNA levels of cytoprotective enzymes (NQO1, HO-1, AKR1C1), and heat shock proteins (HSP27 and HSP70), increased. Conversely, mRNA levels of pro-inflammatory markers (IL-6, IL-1β, COX-2 and tnf-α) decreased. Individually none is sufficiently specific or sensitive, but when grouped by function as two panels, these biomarkers show promise for monitoring pharmacodynamic responses to sulforaphane in both healthy and autistic humans, and providing guidance for biomedical interventions. Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders that, in the United States, is currently estimated to affect 1 out of 59 children who are 8 years old 1. Despite decades of research and advances in our knowledge of the etiologies of ASD, treatments and biomarkers for ASD remain limited 2-5. To date, the primary diagnosis of ASD still relies on observational tools that are by nature subjective 3,6. Genetic and metabolic studies may provide additional clues to specific etiologies or treatments, but there are no generally accepted biological markers for commonly affected cellular pathways in ASD 5,6. Studies over the last two decades have implicated that physiological and metabolic abnormalities, such as immune dysregulation/neuro-inflammation, redox imbalance/oxidative stress, mitochondrial dysfunction, environmental toxicant exposures and gut dysbiosis, are important aspects of the pathophysiology of ASD 6. Closer examination of the biological markers of pathways associated with ASD could be informative regarding its

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“…This variability also makes it difficult for researchers seeking biomarkers or genetic variation in common with most ASD patients. [27,78] The number of patients with ASD is limited, there are no consistent repetitions, the majority of studies are relatively short-term, and therefore there is no strong evidence of long-term effects, evaluation criteria; Lack of important situations such as intelligence assessment, school adaptation and comorbidity constitute the limitations of the mentioned studies. Although bumetanide studies evaluate the effectiveness of boumetanide in autism from many different aspects, there is still a need for more comprehensive double-blind, multicenter randomized and controlled studies.…”

Section: Discussionmentioning

confidence: 99%

“…These; Atypical antipsychotics, propranolol, oxytocin, vasopressin antagonists, arbaclofen, bumetanide and sulforafan. [27] For example, in randomized controlled trials, risperidone and aripiprazole, among atypical antipsychotics, improved irritability and agitation in children and adolescents. However, both drugs caused adverse events such as sedation and weight gain.…”

mentioning

confidence: 99%

Pharmacotherapy and Bumetanide in Autism Treatment

Kalkan

Atasoy

Erbaş³

2020

JEB Med Sci

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Currently, autism spectrum disorder is a common, heterogeneous disease. It is diagnosed through behavioral questionnaires, parent, and doctor observations due to there are no biomarkers. The treatment is mostly carried out through education and behavioral interventions. Proven effective drugs of concomitant diseases can also be added to the treatment regimen if it is necessary. Nevertheless, recent studies have identified several compounds including arbaclofen, oxytocin, sulforaphane, and bumetanide that have an impact on the main symptoms of autism, such as social communication deficits and restrictive/repetitive behaviors. Bumetanide, a proven diuretic, is one of the most studied chemicals in the past decade. In this review; first, diagnosis of autism and tests used for it, are briefly explained, thereafter the pharmacological treatment approaches of autism, the targeted new treatment mechanisms, the association between intracellular chloride concentration with autism are mentioned respectively. After summarising the frequently used animal models, preclinical and clinical studies that focus on the effect of bumetanide, which is the center of this review, on autism were evaluated chronologically.

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Do animal models hold value in Autism spectrum disorder (ASD) drug discovery?

Cited by 17 publications

References 70 publications

The effect of background strain on the behavioral phenotypes of the MDGA2^+/− mouse model of autism spectrum disorder

The effect of background strain on the behavioral phenotypes of the MDGA2^+/− mouse model of autism spectrum disorder

Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder

Pharmacotherapy and Bumetanide in Autism Treatment

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Do animal models hold value in Autism spectrum disorder (ASD) drug discovery?

Cited by 17 publications

References 70 publications

The effect of background strain on the behavioral phenotypes of the MDGA2+/− mouse model of autism spectrum disorder

The effect of background strain on the behavioral phenotypes of the MDGA2+/− mouse model of autism spectrum disorder

Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder

Pharmacotherapy and Bumetanide in Autism Treatment

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The effect of background strain on the behavioral phenotypes of the MDGA2^+/− mouse model of autism spectrum disorder

The effect of background strain on the behavioral phenotypes of the MDGA2^+/− mouse model of autism spectrum disorder