Microrna mechanism of angelman syndrome

The National Institute of Child Health and Human Development awarded The Ohio State University $426,914 on September 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865, Assistance Listing 93.HDR) to investigate microRNA mechanisms in Angelman syndrome.

The research targets dysregulated microRNA expression, specifically the mir-183/96/182 cluster identified as significantly downregulated in Angelman syndrome model mice. The study tests whether augmentation of this microRNA cluster can alleviate core pathologies associated with the neurodevelopmental disorder, including intellectual disability, motor dysfunction, sleep disturbances, EEG abnormalities, and epilepsy. Prior work demonstrated that cannabidiol treatment reversed downregulation of mir-183 and mir-96 in Angelman syndrome model mice, suggesting the cluster's potential role in regulating neurite outgrowth, memory formation, and circadian rhythms. The project aims to identify novel molecular targets for therapeutic intervention where existing treatments address only symptom management.

The award period runs September 1, 2026, through August 31, 2028, with place of performance in Columbus, Ohio. The Ohio State University Office of Sponsored Programs serves as the prime recipient.

Abstract

Angelman syndrome (as) is a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, sleep disturbances, EEG abnormalities, and epilepsy. Despite its significant impact, there is currently no effective therapy for as. Existing treatments primarily involve combinations of medicines to alleviate some of the most debilitating symptoms. There remains an urgent clinical need to identify novel molecular targets that can correct the core pathologies of as. Micrornas (mirnas) are ~22 nucleotide-long noncoding rnas that negatively regulate gene expression by binding to complementary sites in the 3' untranslated region of target messenger rnas. Mirnas play a significant role in regulating gene expression and have been implicated in controlling fundamental neural functions, including neurogenesis, neuronal maturation, synaptic plasticity, and excitatory/inhibitory (e/i) balance. Dysregulated mirna expression is increasingly implicated in the pathogenesis of various neurological and neurodevelopmental disorders. We recently conducted an unbiased genome-wide mirna sequencing analysis using hippocampal tissue collected from adult as model mice and their wild-type (WT) littermate controls. We identified a novel cluster of mirnas, MIR-183/96/182, significantly downregulated in as mice compared to WT controls. Importantly, treatment with cannabidiol, known to ameliorate multiple pathologies in as animal models and individuals with as, reversed the downregulation of MIR-183 and MIR-96, among others, in as model mice. The pivotal role of MIR- 183/96/182 in regulating neurite outgrowth, memory formation, and circadian rhythms suggests its potential involvement in as pathogenesis. Our study aims to treat core as pathologies by targeting MIR-183/96/182. We will test our central hypothesis that MIR-183/96/182 augmentation can alleviate as-associated pathologies and functional alterations in both mouse models and human cortical organoids (hcos). In aim 1, we will profile the differential expression of MIR-183/96/182 in mouse brains and assess the effects of MIR-183/96/182 augmentation on behavioral impairments, EEG abnormalities, and epileptic phenotypes in as model mice. We will also investigate the molecular targets of MIR-183/96/182 in regulating as phenotypes. We will first focus on CACNB4, which mirdb predicts as the top biologically plausible direct target with binding sites for MIR- 183/96/182. To further evaluate the translational potential of this approach, in aim 2, we will validate the differential expression of MIR-183/96/182 using as patients' ipscs-derived hcos and test the effects of MIR- 183/96/182 augmentation on cortical neuronal generation and altered neural properties in UBE3A-deficient organoids. Completing this study will shed light on mirna mechanisms of as pathology and identify MIR- 183/96/182 augmentation as a novel therapeutic approach for as.