Biology subjects

Dindot, S. V.

Publications and source records attributed to Dindot, S. V..

5 recordsLinked to original sources

bioRxiv2026

Elevated Delta Power in a Maternal UBE3A-Deletion Pig Model of Angelman Syndrome

Angelman syndrome is a neurodevelopmental disorder caused by loss of the maternally inherited UBE3A allele and is characterized by severe cognitive, motor, and communication impairments. Increased delta (1- 4 Hz) activity on electroencephalogram (EEG) assessed by visual inspection and by spectral power analysis is a robust feature of the disorder in humans and rodent models and is used as a biomarker of Angelman syndrome. This aspect of the phenotype has not been evaluated in the recently developed pig model of Angelman syndrome. Here, we analyzed scalp EEG recordings from freely moving pigs carrying a maternal UBE3A deletion (UBE3A-/+) across three age groups to determine whether they recapitulate the delta power abnormalities characteristic of the disorder. UBE3A-/+ pigs exhibited elevated delta power during both wakefulness and sleep compared with wild-type littermates, with the largest differences observed during the awake state. The typical increase in delta power that accompanies the transition from wakefulness to sleep was also reduced in UBE3A-/+ pigs. These effects were observed across study groups, demonstrating that the maternal UBE3A-deletion pig model reproduces the elevated delta power EEG phenotype of Angelman syndrome. Our results establish noninvasive scalp EEG as a translationally relevant tool for assessing neural dysfunction in this large-animal model and provide a framework for preclinical therapeutic testing. This work strengthens the utility of the pig model for mechanistic studies and therapeutic development in Angelman syndrome.

neuroscience↗

bioRxiv2025

MRI-Based Quantification of Central Nervous System Tissue and Cerebrospinal Fluid Volumes in Developing Pigs

There is a growing need for alternative animal models to test brain-targeted therapies, and pigs are emerging as a promising option. Their utility, however, depends on reliable estimations of central nervous system (CNS) tissue and cerebrospinal fluid (CSF) volumes, which are essential for translating therapeutic doses between studies in animals and humans. To address this need, we conducted a cross-sectional study of 12 commercial pigs (Sus scrofa) across four age groups (2, 5, 11, and 19 weeks). High-resolution magnetic resonance images (MRI) of the brain and spinal cord were acquired using T2-weighted turbo spin echo with fat saturation and short tau inversion recovery scans. CNS tissue and CSF volumes were segmented and quantified using 3D Slicer, along with additional anatomical measurements. Our findings reveal notable age-related changes, including spinal CSF volume surpassing brain CSF volume in older pigs, highlighting shifts in CSF distribution that may influence dosing and delivery strategies for CNS-targeted therapies. This study provides a reference for future research using pig models in CNS disease studies and underscores the importance of incorporating brain and spinal CSF and CNS volume data into preclinical models.

neuroscience↗

bioRxiv2025

Cell-type-specific dysregulated gene expression in the frontal cortex of an Angelman syndrome pig model

Angelman syndrome is a neurodevelopmental disorder caused by the loss of the maternal allele of the ubiquitin-protein ligase E3A (UBE3A) gene. UBE3A is imprinted with maternal-allelic expression in neurons of the central nervous system (CNS) and biallelic expression in other cell types. Consequently, in Angelman syndrome, UBE3A is substantially reduced in CNS neurons and reduced by half in other cells. It is unclear how cell-type-specific gene expression in the brain is dysregulated in Angelman syndrome, as previous studies have lacked cell type resolution. Using single nuclei RNA-sequencing, we show that gene expression is dysregulated in neuronal subtypes in the frontal cortex of neonatal pigs with a UBE3A maternal deletion. A total of 3,812 unique genes were dysregulated across ten cell type clusters, with most of the dysregulated genes (3,154 genes) in excitatory neurons. Pathway analysis revealed alterations in oxidative phosphorylation, proteasome function, and synaptic function. Additionally, somatostatin (SST) -- a secreted neuropeptide involved in GABAergic inhibition and synaptic plasticity-- was reduced in inhibitory neurons in the cortex and hypothalamus, which correlated with lower circulating SST protein in neonates but not adolescent pigs. Overall, these findings provide greater clarity on the cell-type-specific dysregulation of gene expression and cellular pathways caused by the loss of UBE3A in CNS neurons, expanding our understanding of the molecular pathology in Angelman syndrome.

genetics↗

bioRxiv2025

A preclinical pig model of Angelman syndrome mirrors the early developmental trajectory of the human condition

Angelman syndrome is a neurodevelopmental disorder characterized by severe motor and cognitive deficits. It is caused by the loss of the maternally inherited allele of the imprinted ubiquitin-protein ligase E3A (UBE3A) gene. Rodent models of Angelman syndrome do not fully recapitulate all the symptoms associated with the condition and are limited as a preclinical model for therapeutic development. Here, we show that pigs (Sus scrofa) with a maternally inherited deletion of UBE3A (UBE3A-/+) have altered postnatal behaviors, impaired vocalizations, reduced brain growth, motor incoordination, and ataxia. Neonatal UBE3A-/+ pigs exhibited several symptoms observed in infants with Angelman syndrome, including hypotonia, suckling deficits, and failure to thrive. Collectively, these findings are consistent with the pathophysiology and developmental trajectory observed in individuals with Angelman syndrome. We anticipate that this pig model will advance our understanding of the pathophysiology of Angelman syndrome and be used as a preclinical large animal model for therapeutic development.

genetics↗

bioRxiv2021

Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of the UBE3A-AS transcript

Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. The paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense (UBE3A-AS) transcript, which represents the distal end of the SNHG14 transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we designed and optimized antisense oligonucleotides (ASO) targeting an evolutionarily conserved region demarcating the start of the human UBE3A-AS transcript and show that ASOs targeting this region can reverse imprinting of UBE3A in cultured Angelman syndrome neurons and throughout the CNS of a non-human primate model. Findings from this study advanced the first investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281). SUMMARYHere, we describe the preclinical studies supporting the first investigational molecular therapy for Angelman syndrome to advance into clinical development (ClinicalTrials.gov, NCT04259281).

genetics↗