A Blueprint for Translational Precision Medicine in Autism Spectrum Disorder and Related Neurogenetic Syndromes

Journal of Child and Adolescent Psychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Objectives: Despite growing knowledge of the underlying neurobiology autism spectrum disorder (ASD) and related neurogenetic syndromes, treatment discovery has remained elusive. In this review, we provide a blueprint for translational precision medicine in ASD syndromes. Methods: The trofinetide Rett syndrome (RTT) is described, role nonmammalian, mammalian, stem cell model systems identification molecular targets drug screening discussed. We then framework translating preclinical findings to human clinical trials, including biomarkers selecting evaluating target engagement, discuss how leverage these future development. Results: Multiple have been developed, each with tradeoffs regard suitability high-throughput small molecule screening, conservation across species, behavioral face validity. Future trials should incorporate intermediate phenotypes demonstrate engagement. Factors that contributed approval RTT included replicated mouse models, well-studied natural history syndrome, development RTT-specific outcome measures, strong engagement family community. Conclusions: translation our understanding will require approach, use multiple selection, evaluation trial design strategies address heterogeneity, power, placebo response.

Language: Английский

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Deep learning is widely applicable to phenotyping embryonic development and disease

Development, Journal Year: 2021, Volume and Issue: 148(21)

Published: Nov. 1, 2021

ABSTRACT Genome editing simplifies the generation of new animal models for congenital disorders. However, detailed and unbiased phenotypic assessment altered embryonic development remains a challenge. Here, we explore how deep learning (U-Net) can automate segmentation tasks in various imaging modalities, quantify phenotypes renal, neural craniofacial Xenopus embryos comparison with normal variability. We demonstrate utility this approach polycystic kidneys (pkd1 pkd2) dysmorphia (six1). highlight toto light-sheet microscopy facilitates accurate reconstruction brain structures within X. tropicalis upon dyrk1a six1 loss function or treatment retinoic acid inhibitors. These tools increase sensitivity throughput evaluating developmental malformations caused by chemical genetic disruption. Furthermore, provide library pre-trained networks instructions applying to reader's own datasets. versatility, precision scalability network phenotyping on disease models. By combining learning, framework higher-throughput characterization model organisms. This article has an associated ‘The people behind papers’ interview.

Language: Английский

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Adeno-Associated Viral Tools to Trace Neural Development and Connectivity Across Amphibians

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 16, 2024

Summary The development, evolution, and function of the vertebrate central nervous system (CNS) can be best studied using diverse model organisms. Amphibians, with their unique phylogenetic position at transition between aquatic terrestrial lifestyles, are valuable for understanding origin evolution tetrapod brain spinal cord. Their metamorphic developmental transitions regenerative abilities also facilitate discovery mechanisms neural circuit remodeling replacement. genetic toolkit amphibians, however, remains limited, only a few species having sequenced genomes small number transgenic lines available. In mammals, recombinant adeno-associated viral vectors (AAVs) have become powerful alternative to genome modification visualizing perturbing system. AAVs DNA viruses that enable neuronal transduction in both developing adult animals low toxicity spatial, temporal, cell-type specificity. However, never been shown transduce amphibian cells efficiently. To bridge this gap, we established simple, scalable, robust strategy screen AAV serotypes three distantly-related species: frogs Xenopus laevis Pelophylax bedriagae, salamander Pleurodeles waltl, larval tadpoles post-metamorphic animals. For each species, successfully identified least two capable infecting CNS; no pan-amphibian serotype was identified, indicating rapid tropism. addition, developed an AAV-based targets isochronic cohorts neurons – critical tool parsing assembly. Finally, visualization manipulation circuits, variants retrograde tracing projections Our findings expand amphibians include AAVs, establish generalizable workflow screening non-canonical research organisms, generate testable hypotheses tropism, lay foundation modern cross-species comparisons CNS function, evolution.

Language: Английский

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Label‐free, whole‐brain in vivo mapping in an adult vertebrate with third harmonic generation microscopy

The Journal of Comparative Neurology, Journal Year: 2024, Volume and Issue: 532(4)

Published: April 1, 2024

Abstract Comprehensive understanding of interconnected networks within the brain requires access to high resolution information large field views and over time. Currently, methods that enable mapping structural changes entire in vivo are extremely limited. Third harmonic generation (THG) can resolve myelinated structures, blood vessels, cell bodies throughout without need for any exogenous labeling. Together with deep penetration long wavelengths, this enables brain‐mapping fractions small animals Here, we demonstrate THG microscopy allows non‐invasive label‐free an adult vertebrate, Danionella dracula , which is a miniature species cyprinid fish. We show capability multiple regions particular identification major commissural fiber bundles midbrain hindbrain. These features provide readily discernable landmarks navigation regional‐specific neuronal groups even single neurons during experiments. further how technique easily be coupled fluorescence used as comparative tool studies other similar body such zebrafish ( Danio rerio) tetras Trochilocharax ornatus ). This new evidence, building on previous studies, demonstrates size relative transparency, combined unique capabilities microscopy, vertebrate brain.

Language: Английский

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Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 29, 2024

ABSTRACT The comorbidity of autism spectrum disorders and severe gastrointestinal symptoms is well-established, yet the molecular underpinnings remain unknown. identification high-confidence large-effect risk genes offers opportunity to identify convergent, underlying biology by studying these in context system. Here we show that expression enriched human prenatal gut neurons as well their migratory progenitors, suggesting development and/or function may be disrupted autism-associated pathogenic variants, leading dysfunction. document prevalence issues patients with variants sixteen genes, highlighting dysmotility, consistent potential enteric neuron Using high-throughput diploid frog Xenopus tropicalis , individually target five ( SYNGAP1, CHD8, SCN2A, CHD2 DYRK1A ) observe neuronal progenitor migration for each. More extensive analysis reveals perturbation causes dysmotility vivo which can ameliorated treatment a selective serotonin reuptake inhibitor (escitalopram) or receptor 6 agonist, identified drug screening. This work suggests atypical contributes distress commonly seen individuals increasing signaling productive therapeutic avenue.

Language: Английский

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Adeno-associated viral tools to trace neural development and connectivity across amphibians

Developmental Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

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Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: March 21, 2022

ABSTRACT Many neurodevelopmental genetic disorders, such as Rett syndrome, are caused by a single gene mutation but trigger changes in expression and regulation of numerous other genes. This severely impair functions multiple organs organ systems beyond the central nervous system (CNS), adding to challenge developing broadly effective treatments based on drug target. is further complicated lack sufficiently broad biologically relevant screens, inherent complexity identifying clinically targets responsible for diverse phenotypes. Here, we combined human regulatory network-based computational prediction with vivo screening population-level diversity, CRISPR-edited, Xenopus laevis tadpole model syndrome carry out target-agnostic discovery, which rapidly led identification FDA-approved vorinostat potential repurposing candidate. Vorinostat improved both CNS non-CNS (e.g., gastrointestinal, respiratory, inflammatory) abnormalities pre-clinical mouse syndrome. first treatment demonstrate efficacy across when dosed after onset symptoms, network analysis revealed putative therapeutic mechanism its cross-organ normalizing effects impact acetylation metabolism post-translational modifications microtubules. Although traditionally considered an inhibitor histone deacetylases (HDAC), unexpectedly restored protein hypo- hyperacetylated tissues, suggesting non-HDAC-mediated mechanisms supported proteomic analysis.

Language: Английский

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Characterisation and automated quantification of induced seizure‐related behaviours in Xenopus laevis tadpoles

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 168(12), P. 4014 - 4024

Published: May 2, 2023

Abstract Epilepsy, a clinical diagnosis characterised by paroxysmal episodes known as seizures, affects 1% of people worldwide. Safe and patient‐specific treatment is vital can be achieved the development rapid pre‐clinical models for identified epilepsy genes. Epilepsy result from either brain injury or gene mutations, also induced chemically. Xenopus laevis tadpoles could useful model confirmation variants unknown significance found in patients, drug re‐purposing screens that eventually lead to benefits patients. Here, we characterise quantify seizure‐related behaviours X. arrayed 24‐well plates. To provoke acute seizure behaviours, were chemically with pentylenetetrazole (PTZ) 4‐aminopyridine (4‐AP). test capacity adapt this method testing, exposed anti‐seizure valproate (VPA). Four seizure‐like described manually quantified, two these (darting, circling) accurately detected automatically, using video analysis software TopScan. Additionally, recorded swimming trajectories mean velocity. Automatic detection showed PTZ 4‐AP darting behaviour increased velocity compared untreated controls. Both parameters significantly reduced presence VPA. In particular, was shown sensitive measure epileptic activity. While not automatically detect full range shows promise future studies since well‐characterised genetically tractable organism. image

Language: Английский

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Information integration during bioelectric regulation of morphogenesis of the embryonic frog brain

iScience, Journal Year: 2023, Volume and Issue: 26(12), P. 108398 - 108398

Published: Nov. 4, 2023

Language: Английский

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Production and characterization of monoclonal antibodies to Xenopus proteins

Development, Journal Year: 2023, Volume and Issue: 150(4)

Published: Feb. 14, 2023

Monoclonal antibodies are powerful and versatile tools that enable the study of proteins in diverse contexts. They often utilized to assist with identifying subcellular localization characterizing function target interest. However, because there can be considerable sequence diversity between orthologous Xenopus mammals, produced against mouse or human do not recognize counterparts. To address this issue, we refined existing protocols produce monoclonal directed Here describe several approaches for generation useful anti-Xenopus multiple their validation various experimental approaches. These novel now available research community through Developmental Study Hybridoma Bank (DSHB).

Language: Английский

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