Improving gene therapy for Angelman syndrome with secreted human UBE3A
Open accessAbstract
The rare genetic neurodevelopmental disease Angelman syndrome (AS) is caused by the loss of function of UBE3A, a ubiquitin ligase. The disease results in a lifetime of severe symptoms, including intellectual disability and motor impairments for which there are no effective treatments. One avenue of treatment for AS is the use of gene therapy to reintroduce a functional copy of the UBE3A gene. Our group had previously shown that recombinant adeno-associated virus (rAAV) expressing mouse Ube3a could rescue deficits in a mouse model of AS. Here, we expand on this work and show that this approach could be successfully replicated in a second AS model using the human UBE3A gene. Furthermore, we address the challenge of limited vector distribution in the brain by developing a novel modified form of UBE3A. This modified protein, termed STUB, was designed with a secretion signal and a cell-penetrating peptide. This allowed transduced cells to act as factories for the production of UBE3A protein that could be taken up by neighboring non-transduced cells, thus increasing the number of neurons receiving the therapeutic protein. Combining this construct with intracerebroventricular injections to maximize rAAV distribution within the brain, we demonstrate that this novel approach improves the recovery of behavioral and electrophysiological deficits in the AS rat model. More importantly, a comparison of rAAV-STUB to a rAAV expressing the normal human UBE3A gene showed that STUB was a more effective therapeutic. These data suggest that rAAV-STUB is a new potential approach for the treatment of AS.
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Overexpression of UBE3A appears to disturb synaptic homeostasis through excessive ubiquitin pathway activity, yet often spares the severe somatic anomalies that characterize Angelman syndrome.
“Overexpression of UBE3A appears to disturb synaptic homeostasis through excessive ubiquitin pathway activity, yet often spares the severe somatic anomalies that characterize Angelman syndrome (Nenninger et al., 2022).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Nenninger et al., 2022
The Introduction (page unavailable) identifies UBE3A as an E3 ubiquitin ligase and links Angelman syndrome chiefly to its loss. The Discussion (page unavailable) describes improved synaptic function after UBE3A gene therapy, but neither it nor passages retrieved for overexpression, excessive ubiquitin activity, and somatic anomalies addresses the claimed effects of UBE3A overexpression. (LLM, conf=0.74)
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Research works printed but not linked: 23
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Cited by
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Qing, Z., Yin, Z., Chen, B., Rao, Z., Yin, D., Li, D., Lu, Y., Shi, M., Li, S., Xu, Y., et al. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1964684
“Overexpression of UBE3A appears to disturb synaptic homeostasis through excessive ubiquitin pathway activity, yet often spares the severe somatic anomalies that characterize Angelman syndrome (Nenninger et al., 2022).”
- Authors
- Nenninger, A. W., Willman, M., Willman, J., Stewart, E., Mesidor, P., Novoa, M., Morrill, N. K., Alvarez, L., Joly-Amado, A., Peters, M. M., Gulick, D., & Nash, K. R.
- Affiliations
- University of South Florida (US)
- Corresponding author
- Nash, Kevin R.
- ORCID
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2022-07
- Volume
- 19
- Issue
- 4
- Pages
- 1329-1339
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC9587189
- OpenAlex
- W4229458256
- Cited by
- 15
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 2
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for Angelman Syndrome Therapeutics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Angelman syndrome, UBE3A, gene therapy, recombinant adeno-associated virus, cell-penetrating peptides, secretion signal, intracerebroventricular administration, mouse and rat models, intellectual disability, motor impairment, ubiquitin ligase
- MeSH terms
- Animals, Humans, Ubiquitins, Genetic Therapy, Angelman Syndrome, Ubiquitin-Protein Ligases, Mice, Rats, Cell-Penetrating Peptides
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