MECP2 Isoform-Specific Vectors with Regulated Expression for Rett Syndrome Gene Therapy
Open accessAbstract
BACKGROUND: Rett Syndrome (RTT) is an Autism Spectrum Disorder and the leading cause of mental retardation in females. RTT is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment. Our objective is to develop viral vectors for MECP2 gene transfer into Neural Stem Cells (NSC) and neurons suitable for gene therapy of Rett Syndrome. METHODOLOGY/PRINCIPAL FINDINGS: We generated self-inactivating (SIN) retroviral vectors with the ubiquitous EF1alpha promoter avoiding known silencer elements to escape stem-cell-specific viral silencing. High efficiency NSC infection resulted in long-term EGFP expression in transduced NSC and after differentiation into neurons. Infection with Myc-tagged MECP2-isoform-specific (E1 and E2) vectors directed MeCP2 to heterochromatin of transduced NSC and neurons. In contrast, vectors with an internal mouse Mecp2 promoter (MeP) directed restricted expression only in neurons and glia and not NSC, recapitulating the endogenous expression pattern required to avoid detrimental consequences of MECP2 ectopic expression. In differentiated NSC from adult heterozygous Mecp2(tm1.1Bird)+/- female mice, 48% of neurons expressed endogenous MeCP2 due to random inactivation of the X-linked Mecp2 gene. Retroviral MECP2 transduction with EF1alpha and MeP vectors rescued expression in 95-100% of neurons resulting in increased dendrite branching function in vitro. Insulated MECP2 isoform-specific lentiviral vectors show long-term expression in NSC and their differentiated neuronal progeny, and directly infect dissociated murine cortical neurons with high efficiency. CONCLUSIONS/SIGNIFICANCE: MeP vectors recapitulate the endogenous expression pattern of MeCP2 in neurons and glia. They have utility to study MeCP2 isoform-specific functions in vitro, and are effective gene therapy vectors for rescuing dendritic maturation of neurons in an ex vivo model of RTT.
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WPRE showed no effects on transgene expression in both in vitro and in vivo when combined with either EF-1α or CAG promoter in the presence of an intron element.
“Controversially, WPRE showed no effects on transgene expression in both in vitro and in vivo when combined with either EF-1α or CAG promoter in the presence of an intron element [28, 29].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [29]
The Results section on Mecp2 promoter expression reports experiments with EF1α and MeP, but does not assess WPRE’s effect on transgene expression. Searches for WPRE and for the claimed CAG-promoter and intron combination found no passage addressing that comparison in our copy; no page numbers are available. (LLM, conf=0.76)
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Retts Syndrom og MECP2 Duplication Syndrome Det kliniske bildet og betydningen av MeCP2
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Self-citation
- Authors
- Rastegar, M., Hotta, A., Pasceri, P., Makarem, M., Cheung, A. Y. L., Elliott, S., Park, K. J., Adachi, M., Jones, F. S., Clarke, I. D., Dirks, P., & Ellis, J.
- Affiliations
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- Neurosciences Institute (US)
- Corresponding author
- Ellis, James
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-08-27
- Volume
- 4
- Issue
- 8
- Pages
- e6810
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2728539
- OpenAlex
- W2156696931
- Cited by
- 79
- References
- 53
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 7 · 2014: 7 · 2013: 7 · 2012: 11
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- International Rett Syndrome Foundation
- National Science Council
- Hospital for Sick Children
- Canadian Institutes of Health Research (92090)
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Rett syndrome, MeCP2, gene therapy vectors, retroviral vectors, lentiviral vectors, neural stem cells, neuronal differentiation, EF1α promoter, dendritic cell maturation, heterochromatin, ex vivo gene therapy
- MeSH terms
- Animals, Female, Gene Expression Regulation, Genetic Vectors, Humans, Promoter Regions, Genetic, Transduction, Genetic, Genetic Therapy, Rett Syndrome, Lentivirus, Mice, Methyl-CpG-Binding Protein 2
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