Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome
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Abstract
Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.
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Nsdhl downregulation has also been reported in an independent study of Rett syndrome.
“Interestingly, Nsdhl downregulation has also been reported in an independent study of Rett syndrome (Luoni et al., 2020), further supporting the reproducibility of this finding.”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Luoni et al., 2020
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Bido, S., Muggeo, S., Massimino, L., Marzi, M. J., Giannelli, S. G., Melacini, E., Nannoni, M., Gambarè, D., Bellini, E., Ordazzo, G., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26519-x · Cited by 190 · see citing works
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Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome
Postogna, F. M., Giancroce, N., Cabasino, C., Biella, F., Roggero, O. M., Breccia, M., Morelli, L., Colombo, D., Arcari, A., Lunghi, G., et al. (2026) · doi:10.64898/2026.07.29.741426 · Cited by 1 · see citing works
- Authors
- Luoni, M., Giannelli, S., Indrigo, M. T., Niro, A., Massimino, L., Iannielli, A., Passeri, L., Russo, F., Morabito, G., Calamita, P., Gregori, S., Deverman, B., & Broccoli, V.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- Stanley Center for Psychiatric Research (US)
- Corresponding author
- Broccoli, Vania
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-03-24
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7117907
- OpenAlex
- W3012777612
- Cited by
- 65
- References
- 12
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 9 · 2023: 13 · 2022: 11 · 2021: 10 · 2020: 7
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fondazione Telethon (GGP19038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- 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
- Keywords
- Rett syndrome, MeCP2, RNA destabilization, AAV-PHP.eB, adeno-associated virus gene therapy, locomotor activity, lifespan, immunosuppression, sex differences in immune response, neurodevelopmental disorders
- MeSH terms
- Animals, Brain, Disease Models, Animal, Gene Expression Regulation, Mice, Transgenic, Mutation, Genetic Therapy, Rett Syndrome, Gene Expression, Transgenes, Methyl-CpG-Binding Protein 2
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