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Citations to this article

Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice
Matthew C. Judson, … , Steven J. Gray, Benjamin D. Philpot
Matthew C. Judson, … , Steven J. Gray, Benjamin D. Philpot
Published October 22, 2021
Citation Information: JCI Insight. 2021;6(20):e144712. https://doi.org/10.1172/jci.insight.144712.
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Research Article Neuroscience Therapeutics Article has an altmetric score of 87

Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice

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Abstract

Loss of the maternal UBE3A allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on reinstating dual-isoform expression of human UBE3A (hUBE3A) in the developing brain. Kozak sequence engineering of our codon-optimized vector (hUBE3Aopt) enabled translation of both short and long hUBE3A protein isoforms at a near-endogenous 3:1 (short/long) ratio, a feature that could help to support optimal therapeutic outcomes. To model widespread brain delivery and early postnatal onset of hUBE3A expression, we packaged the hUBE3Aopt vector into PHP.B capsids and performed intracerebroventricular injections in neonates. This treatment significantly improved motor learning and innate behaviors in AS mice, and it rendered them resilient to epileptogenesis and associated hippocampal neuropathologies induced by seizure kindling. hUBE3A overexpression occurred frequently in the hippocampus but was uncommon in the neocortex and other major brain structures; furthermore, it did not correlate with behavioral performance. Our results demonstrate the feasibility, tolerability, and therapeutic potential for dual-isoform hUBE3A gene transfer in the treatment of AS.

Authors

Matthew C. Judson, Charles Shyng, Jeremy M. Simon, Courtney R. Davis, A. Mattijs Punt, Mirabel T. Salmon, Noah W. Miller, Kimberly D. Ritola, Ype Elgersma, David G. Amaral, Steven J. Gray, Benjamin D. Philpot

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Total citations by year

Year: 2025 2024 2023 2022 Total
Citations: 2 9 4 4 19
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Citations to this article (19)

Title and authors Publication Year
Courtship and distress ultrasonic vocalizations are disrupted in a mouse model of Angelman syndrome
Guoynes CD, Pavalko G, Sidorov MS
Research Square 2025
NEXMIF overexpression is associated with autism-like behaviors and alterations in dendritic arborization and spine formation in mice
Odamah K, Nishizawa Criales MT, Man HY
Frontiers in Neuroscience 2025
Modelling phenotypes, variants and pathomechanisms of syndromic diseases in different systems
Gregor A, Zweier C
medizinische genetik 2024
Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey
Gonzalez Ramirez C, Salvador SG, Patel RK, Clark S, Miller NW, James LM, Ringelberg NW, Simon JM, Bennett J, Amaral DG, Burette AC, Philpot BD
Frontiers in neuroanatomy 2024
Ube3a unsilencer for the potential treatment of Angelman syndrome
Vihma H, Li K, Welton-Arndt A, Smith AL, Bettadapur KR, Gilmore RB, Gao E, Cotney JL, Huang HC, Collins JL, Chamberlain SJ, Lee HM, Aubé J, Philpot BD
Nature Communications 2024
Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels
Montani C, Balasco L, Pagani M, Alvino FG, Barsotti N, de Guzman AE, Galbusera A, de Felice A, Nickl-Jockschat TK, Migliarini S, Casarosa S, Lau P, Mattioni L, Pasqualetti M, Provenzano G, Bozzi Y, Lombardo MV, Gozzi A
Science Advances 2024
Neuronal UBE3A substrates hold therapeutic potential for Angelman syndrome
Krzeski JC, Judson MC, Philpot BD
Current opinion in neurobiology 2024
AAV vector-derived elements integrate into Cas9-generated double-strand breaks and disrupt gene transcription.
Bazick HO, Mao H, Niehaus JK, Wolter JM, Zylka MJ
Molecular therapy : the journal of the American Society of Gene Therapy 2024
Differences in structure, dynamics, and zinc coordination between isoforms of human ubiquitin ligase UBE3A
Bregnard TA, Fairchild D, Chen X, Erlandsen H, Tarasov SG, Walters KJ, Korzhnev DM, Bezsonova I
The Journal of Biological Chemistry 2024
Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications
Ye D, Chukwu C, Yang Y, Hu Z, Chen H
Advanced drug delivery reviews 2024
Understanding ubiquitination in neurodevelopment by integrating insights across space and time.
Ambrozkiewicz MC, Lorenz S
Nature structural & molecular biology 2024
Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome
Dongwon Lee, Wu Chen, Heet Kaku, Xinming Zhuo, Eugene Chao, Armand Soriano, Allen Kuncheria, Stephanie Flores, Joo Hyun Kim, Frank Rigo, Paymaan Jafar-nejad, Arthur Beaudet, Matthew Caudill, Mingshan Xue
eLife 2023
Transcriptional reprogramming restores UBE3A brain-wide and rescues behavioral phenotypes in an Angelman syndrome mouse model
Henriette O'Geen, Ulrika Beitnere, Miranda Garcia, Anna Adhikari, David Cameron, Timothy Fenton, Nycole Copping, Peter Deng, Samantha Lock, Julian Halmai, Isaac Villegas, Jiajian Liu, Danhui Wang, Gregory Davis, Kyle Fink, Jill Silverman, David Segal
Molecular Therapy 2023
Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases
Chaudhary P, Proulx J, Park IW
Virus Research 2023
AAV-based in vivo gene therapy for neurological disorders.
Ling Q, Herstine JA, Bradbury A, Gray SJ
Nature reviews. Drug discovery 2023
Sex‐dependent influence of postweaning environmental enrichment in Angelman syndrome model mice
J Cosgrove, L Kelly, E Kiffmeyer, A Kloth
Brain and Behavior 2022
Multidimensional analysis of behavior predicts genotype with high accuracy in a mouse model of Angelman syndrome
Tanas JK, Kerr DD, Wang L, Rai A, Wallaard I, Elgersma Y, Sidorov MS
Translational Psychiatry 2022
Dissociating motor impairment from five-choice serial reaction time task performance in a mouse model of Angelman syndrome
Negrón-Moreno PN, Diep DT, Guoynes CD, Sidorov MS
Frontiers in behavioral neuroscience 2022
Promising therapeutic aspects in human genetic imprinting disorders
Chao Y, Qin Y, Zou X, Wang X, Hu C, Xia F, Zou C
Clinical Epigenetics 2022

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